WO2022131026A1 - Use of cyclic dipeptides in production of agent for inhibiting decline in cognitive function or ameliorating cognitive dysfunction - Google Patents
Use of cyclic dipeptides in production of agent for inhibiting decline in cognitive function or ameliorating cognitive dysfunction Download PDFInfo
- Publication number
- WO2022131026A1 WO2022131026A1 PCT/JP2021/044490 JP2021044490W WO2022131026A1 WO 2022131026 A1 WO2022131026 A1 WO 2022131026A1 JP 2021044490 W JP2021044490 W JP 2021044490W WO 2022131026 A1 WO2022131026 A1 WO 2022131026A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyclo
- pro
- phe
- function
- decline
- Prior art date
Links
- 230000007423 decrease Effects 0.000 title claims abstract description 107
- 230000003920 cognitive function Effects 0.000 title claims abstract description 102
- 208000010877 cognitive disease Diseases 0.000 title claims abstract description 77
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 59
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 37
- 108010016626 Dipeptides Proteins 0.000 title description 53
- 125000004122 cyclic group Chemical group 0.000 title description 52
- OWOHLURDBZHNGG-YFKPBYRVSA-N (8ar)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione Chemical compound O=C1CNC(=O)[C@@H]2CCCN12 OWOHLURDBZHNGG-YFKPBYRVSA-N 0.000 claims abstract description 78
- JUAPMRSLDANLAS-HOTGVXAUSA-N cyclo(L-phenylalanyl-L-phenylalanyl) Chemical compound C([C@@H]1NC([C@@H](NC1=O)CC=1C=CC=CC=1)=O)C1=CC=CC=C1 JUAPMRSLDANLAS-HOTGVXAUSA-N 0.000 claims abstract description 78
- 108010039669 cyclo(phenylalanyl-phenylalanyl) Proteins 0.000 claims abstract description 78
- JUAPMRSLDANLAS-UHFFFAOYSA-N cyclo-L-Phe-L-Phe Natural products O=C1NC(CC=2C=CC=CC=2)C(=O)NC1CC1=CC=CC=C1 JUAPMRSLDANLAS-UHFFFAOYSA-N 0.000 claims abstract description 78
- 108010001140 cyclo(glycylprolyl) Proteins 0.000 claims abstract description 76
- GIAZPLMMQOERPN-YUMQZZPRSA-N Val-Pro Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(O)=O GIAZPLMMQOERPN-YUMQZZPRSA-N 0.000 claims abstract description 74
- NAKUGCPAQTUSBE-IUCAKERBSA-N cyclo(L-His-L-Pro) Chemical compound C([C@@H]1NC([C@@H]2CCCN2C1=O)=O)C1=CN=CN1 NAKUGCPAQTUSBE-IUCAKERBSA-N 0.000 claims abstract description 74
- 108010017068 histidyl-proline diketopiperazine Proteins 0.000 claims abstract description 74
- 230000006386 memory function Effects 0.000 claims abstract description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 79
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 43
- 230000006870 function Effects 0.000 claims description 43
- 235000013361 beverage Nutrition 0.000 claims description 31
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 28
- 229940127557 pharmaceutical product Drugs 0.000 claims description 28
- 235000013305 food Nutrition 0.000 claims description 27
- 230000015654 memory Effects 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 23
- 210000004556 brain Anatomy 0.000 claims description 17
- 230000005764 inhibitory process Effects 0.000 claims description 17
- 206010061218 Inflammation Diseases 0.000 claims description 15
- 230000004054 inflammatory process Effects 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 13
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 13
- 230000032683 aging Effects 0.000 claims description 12
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 10
- 208000026139 Memory disease Diseases 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 7
- 230000007497 verbal memory Effects 0.000 claims description 7
- 230000010330 visuo-spatial memory Effects 0.000 claims description 7
- 230000002708 enhancing effect Effects 0.000 claims description 6
- 230000001737 promoting effect Effects 0.000 claims description 6
- 230000003936 working memory Effects 0.000 claims description 4
- 230000006999 cognitive decline Effects 0.000 claims description 3
- 230000037410 cognitive enhancement Effects 0.000 claims description 3
- 238000007596 consolidation process Methods 0.000 claims description 3
- 230000007787 long-term memory Effects 0.000 claims description 3
- 230000014759 maintenance of location Effects 0.000 claims description 3
- 230000006403 short-term memory Effects 0.000 claims description 3
- 210000004027 cell Anatomy 0.000 description 36
- 239000002158 endotoxin Substances 0.000 description 20
- 229920006008 lipopolysaccharide Polymers 0.000 description 20
- 230000000694 effects Effects 0.000 description 18
- 201000010099 disease Diseases 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 10
- 230000002025 microglial effect Effects 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 230000002757 inflammatory effect Effects 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- -1 inorganic acid salt Chemical class 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 239000003531 protein hydrolysate Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 108010009736 Protein Hydrolysates Proteins 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010003062 Apraxia Diseases 0.000 description 3
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 201000007201 aphasia Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 235000013402 health food Nutrition 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- CMFNMSMUKZHDEY-UHFFFAOYSA-N peroxynitrous acid Chemical compound OON=O CMFNMSMUKZHDEY-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000001755 vocal effect Effects 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 2
- 102000000013 Chemokine CCL3 Human genes 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical class CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 206010070246 Executive dysfunction Diseases 0.000 description 2
- 201000011240 Frontotemporal dementia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- OWOHLURDBZHNGG-UHFFFAOYSA-N Hexahydropyrrolo[1,2-a]pyrazine-1,4-dione Chemical compound O=C1CNC(=O)C2CCCN12 OWOHLURDBZHNGG-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical class NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 230000001668 ameliorated effect Effects 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 210000001612 chondrocyte Anatomy 0.000 description 2
- 108010083188 cyclo(prolylglycyl) Proteins 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000007837 multiplex assay Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 235000013594 poultry meat Nutrition 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OBSLWIKITOYASJ-YDEIVXIUSA-N (3r,4r,5s,6r)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical class CN[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OBSLWIKITOYASJ-YDEIVXIUSA-N 0.000 description 1
- 208000006888 Agnosia Diseases 0.000 description 1
- 241001047040 Agnosia Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 101710155856 C-C motif chemokine 3 Proteins 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 108700012434 CCL3 Proteins 0.000 description 1
- 101100394230 Caenorhabditis elegans ham-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 102000001326 Chemokine CCL4 Human genes 0.000 description 1
- 108010055165 Chemokine CCL4 Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 102100023688 Eotaxin Human genes 0.000 description 1
- 101710139422 Eotaxin Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 102100034221 Growth-regulated alpha protein Human genes 0.000 description 1
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 1
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108050003558 Interleukin-17 Proteins 0.000 description 1
- 102000013691 Interleukin-17 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010002335 Interleukin-9 Proteins 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100045395 Mus musculus Tap1 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 108010064851 Plant Proteins Proteins 0.000 description 1
- 108010066207 Poultry Proteins Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 208000037132 Subdural Chronic Hematoma Diseases 0.000 description 1
- 208000002667 Subdural Hematoma Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- 238000010162 Tukey test Methods 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 208000025698 brain inflammatory disease Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 235000014171 carbonated beverage Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 235000016213 coffee Nutrition 0.000 description 1
- 235000013353 coffee beverage Nutrition 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000015897 energy drink Nutrition 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 235000019985 fermented beverage Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000020510 functional beverage Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000010365 information processing Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 235000019226 kombucha tea Nutrition 0.000 description 1
- 230000008449 language Effects 0.000 description 1
- 235000021056 liquid food Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000005056 memory consolidation Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 235000019520 non-alcoholic beverage Nutrition 0.000 description 1
- 201000003077 normal pressure hydrocephalus Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical group O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 1
- 235000021118 plant-derived protein Nutrition 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000013322 soy milk Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
Definitions
- the present invention relates to use of cyclic dipeptides in the production of an agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- the present invention also relates to a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, and a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- Improvement in cognitive function such as memory function is desired by many people regardless of generation. Recently, an aging-related decline in cognitive function has been a problem in countries where the elderly ratio in the population is high, and search has been made for a component capable of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction through daily intake of the component as a food, beverage, or the like.
- Patent Literature 1 discloses an agent containing Cyclo(Gly-Pro) for inhibiting a decline in cognitive function and/or for improving cognitive function.
- oral intake of the agent for inhibiting a decline in cognitive function and/or improving cognitive function by a human can inhibit a decline in attention/concentration, language ability, and visuospatial/constructional ability, and/or can improve these abilities.
- Patent Literature 1 JP 6598412 B
- the present invention aims to provide an agent effective in inhibiting a decline in cognitive function such as memory function or ameliorating cognitive dysfunction.
- the present invention also aims to provide a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- the present invention also aims to provide a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- the present invention relates to, but is not limited to, use, a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, and a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, for example, which are described as follows.
- a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction and a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, for example, which are described as follows.
- the cognitive dysfunction is aging-related cognitive dysfunction.
- the cognitive function includes at least one selected from the group consisting of memory function, executive function, attention, and concentration.
- the memory function includes at least one selected from the group consisting of verbal memory function, nonverbal memory function, visuospatial memory function, gist memory function, and working memory function.
- the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of inflammation in the brain.
- the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit the inflammation in the brain by inhibition of the production of nitric oxide.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction containing: Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) as active ingredients.
- a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction including: administering or feeding Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
- the present invention provides an agent effective in inhibiting a decline in cognitive function such as memory function or ameliorating cognitive dysfunction.
- the present invention also provides a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction and the like.
- the agent and the composition of the present invention can be used as foods or beverages, pharmaceutical products, or the like for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- Cyclic dipeptides are ingestible as foods, beverages, pharmaceutical products, or the like by humans, and are advantageously highly safe.
- the present invention also provides a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- the present invention relates to use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the production of an agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- a combination use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) shows excellent effects of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can be used as active ingredients of the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction usually contains Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) as active ingredients.
- Cyclo(Phe-Phe) (cyclo-phenylalanyl-phenylalanine), Cyclo(Gly-Pro) (cyclo-glycyl-proline), Cyclo(His-Pro) (cyclo-histidyl-proline), and Cyclo(Val-Pro) (cyclo-valyl-proline) are cyclic dipeptides.
- cyclic dipeptide refers to a compound whose structural units are amino acids and which has a diketopiperazine structure produced by dehydration condensation of an amino group of an amino acid at the N-terminal side and a carboxy group of an amino acid at the C-terminal side.
- Cyclo(Gly-Pro) and Cyclo(Pro-Gly) represent an identical cyclic dipeptide.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro) and Cyclo(Val-Pro) can be used in the form of a salt with an inorganic acid or an organic acid or a salt with an inorganic base or an organic base in the present invention.
- Such an acid or a base can be selected based on the application of the salt.
- the inorganic acid salt include hydrochloride, nitrate, sulfate, methanesulfonate, and p-toluenesulfonate.
- Examples of the organic acid salt include salts with dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, and salts with monocarboxylic acids such as acetic acid, propionic acid, and butyric acid.
- Examples of the inorganic base include hydroxides, carbonates, and bicarbonates of sodium, lithium, calcium, magnesium, and aluminium and ammonia.
- Examples of the salt with the organic base include mono-, di-, or tri-alkylamine salts such as salts of methylamine, dimethylamine, and triethylamine, mono-, di-, or tri-hydroxyalkylamine salts, guanidine salt, and N-methylglucosamine salt.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) may be derived from extracts of natural products such as an extract obtained by heat treatment of natural product or hydrolyzed protein, or may be artificially synthesized products.
- these cyclic dipeptides are derived from the extracts of natural products, they can be obtained, for example, by heating protein or protein hydrolysates such as plant protein hydrolysates, poultry protein hydrolysates or collagen hydrolysates in water.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) may be used in the form of protein hydrolysates containing these cyclic dipeptides, or may be used in the form of concentrates, dry powder, or purified products thereof. Cyclic dipeptides are ingestible as foods or beverages and are highly safe.
- the above protein hydrolysates or heat-treated product thereof can be used to add Cyclo (Phe-Phe), Cyclo (Gly-Pro), Cyclo (His-Pro) and Cyclo (Val-Pro) to the agent or composition.
- the cognitive function refers to the brain function such as memory function, learning ability, memory consolidation, executive function, attention (attention function), and concentration.
- the cognitive dysfunction means partial or entire failure of the cognitive function.
- the phrase “inhibiting a decline in cognitive function” encompasses maintaining cognitive function, slowing down the speed of decline in cognitive function, stopping decline in cognitive function, and the like.
- the phrase “ameliorating cognitive dysfunction” encompasses alleviating (moderating) the degree of cognitive dysfunction, recovering cognitive function, improving cognitive function, and the like.
- the phrase “inhibiting a decline in cognitive function or ameliorating cognitive dysfunction” encompasses inhibiting a decline in part of cognitive function or ameliorating part of cognitive dysfunction.
- the term “recovering” encompasses at least partial recovering.
- Examples of causes of the decline in cognitive function or cognitive dysfunction include aging; neurodegenerative diseases such as Alzheimer's disease, Pick's disease, and diffuse Lewy body disease; brain diseases such as cerebral infarction, cerebral hemorrhage, chronic subdural hematoma, brain tumor, encephalitis, and normal pressure hydrocephalus; dementia such as vascular dementia and frontotemporal dementia; and Creutzfeldt-Jakob disease.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to ameliorate aging-related cognitive dysfunction.
- the aging-related cognitive dysfunction may be aging-related cognitive dysfunction among middle-aged and older people.
- the middle-aged and older people include the elderly.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to inhibit a decline in cognitive function or ameliorate cognitive dysfunction, the cognitive function being at least one selected from the group consisting of memory function, executive function, attention, and concentration.
- the memory function is a function for retaining information from past experiences and retrieving the information for use at a later time.
- the memory function is classified into, for example, verbal memory function, nonverbal memory function, visuospatial memory function, gist memory function, and working memory function.
- the executive function is a function for making decision, formulating and carrying out plans to achieve goals, and is an essential function for people to behave socially, independently, and creatively.
- the executive function compares various kinds of information such as visual, auditory, and olfactory information to information from past experiences and coordinate the information in the frontal lobe.
- the attention is a function for selecting information from a large amount of information. It is an information selective processing function for selectively processing necessary information by not assigning processing resources to unnecessary information in order to effectively use limited processing resources in the brain.
- the concentration is a function for investing mental effort or focusing effectively on the task at hand while ignoring distractions in any given situation.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to inhibit a decline in memory function or improve memory function, and can be more suitably used to inhibit a decline in verbal memory function, nonverbal memory function, visuospatial memory function, gist memory function, and working memory function, or improve these functions.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) when used in combination exhibit an excellent action to inhibit the production of nitric oxide (NO).
- the effect of inhibiting the production of NO, which is obtainable by the combination of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) is a significant effect that cannot be predicted from the effect of inhibiting the production of NO which is obtainable when each of these cyclic dipeptides is used alone.
- peroxynitrite in an aging-related inflammatory condition, NO is attached to superoxide to form peroxynitrite (ONOO - ).
- Peroxynitrite in the brain is known to cause, for example, inflammation in the brain such as oxidative stress in the brain and neuroinflammation. Inflammation in the brain is considered to be one of the causes of a decline in cognitive function in Alzheimer's disease and the like.
- inhibition of the production of peroxynitrite by inhibition of the production of NO is considered to inhibit a decline in cognitive function.
- Intake or administration of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can inhibit the production of NO and in turn can inhibit inflammation in the brain.
- Inhibition of inflammation in the brain can inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
- the action of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to inhibit the production of NO is observed in, for example, microglial cells and the like.
- Microglial cells are a type of glial cells in the central nervous system, and are considered to be the major central immunocompetent cells.
- An increase in the production of NO in microglial cells is known to relate to a decline in cognitive function.
- Inhibition of the production of NO in microglial cells inhibits inflammation in the brain, which in turn can inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can be used to inhibit inflammation in the brain so to as inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used, for example, to inhibit a decline in cognitive function associated with inflammation in the brain or ameliorate cognitive dysfunction associated with inflammation in the brain.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used to inhibit inflammation in the brain by inhibition of the production of NO so as to inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) when used in combination have an excellent action to inhibit the production of inflammatory markers.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can be suitably used to inhibit the production of particularly tumor necrosis factor- ⁇ (TNF- ⁇ ) among inflammatory markers.
- the effect of inhibiting the production of TNF- ⁇ which is obtainable by the combination of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), is a significant effect that cannot be predicted from the effect of inhibiting the production of inflammatory markers which is obtainable when each of these cyclic dipeptides is used alone.
- the action of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to inhibit the production of inflammatory markers is observed in, for example, microglial cells.
- An increase in the production of TNF- ⁇ is known to relate to a decline in cognitive function.
- inflammation in the brain is inhibited by inhibition of the production of TNF- ⁇ in microglial cells, which in turn can inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of the production of TNF- ⁇ , and can be suitably used for such purposes.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used to prevent or ameliorate a condition or disease that can be prevented or ameliorated by inhibition of a decline in cognitive function or amelioration of cognitive dysfunction.
- a condition or disease may be a condition or disease that shows a decline in cognitive function, or a condition associated with a decline in cognitive function.
- Examples thereof include a decline in memory, memory disorders (forgetfulness), aphasia (inability to formulate words), apraxia, agnosia (e.g., getting lost in a familiar place), a decline in verbal and non-verbal learning, a decline in auditory and visual processing, a decline in problem solving, a decline in executive function, executive dysfunction (inability to formulate and carry out plans), a decline in concentration, a decline in attention, a decline in judgement, a decline in spatial awareness, a decline in cognitive flexibility, and a decline in information processing speed.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to prevent or ameliorate a decline in memory, memory disorders, aphasia, apraxia, executive dysfunction, a decline in executive function, a decline in concentration, a decline in attention, and the like.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to prevent or ameliorate an aging-related decline in memory, memory disorders, aphasia, apraxia, verbal learning, a decline in executive function, a decline in concentration, a decline in attention, and the like.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used to prevent or ameliorate the above conditions or diseases by inhibition of the production of NO.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used to prevent or ameliorate the above conditions or diseases by inhibition of the production of TNF- ⁇ .
- prevention of a condition or disease encompasses preventing the onset of a condition or disease, delaying the onset of a condition or disease, reducing the incidence, reducing the onset risk, and the like.
- amelioration of a condition or disease encompasses helping a subject recover from a condition or disease, alleviating a symptom of a condition or disease, changing a symptom of a condition or disease for the better, delaying or preventing the progress of a condition or disease, and the like.
- the agent containing Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) is applicable for either therapeutic use (medical use) or non-therapeutic use (non-medical use).
- the "non-therapeutic" is a concept that does not include medical activities, i.e., a concept that does not include surgery, therapy, or diagnosis of humans.
- the agent can be provided directly as a composition, or can be provided as a composition containing the agent.
- the agent may be either for oral administration or parenteral administration.
- the agent is for oral administration.
- the agent can be provided, for example, as a food or beverage, pharmaceutical product, quasi-pharmaceutical product, or feed.
- a food or beverage, or pharmaceutical product is preferred.
- the agent can be used by being added to a food or beverage, pharmaceutical product, quasi-pharmaceutical product, feed, or the like.
- components usable in a food or beverage e.g., food or beverage materials and optional food or beverage additives
- Non-limiting examples of the food or beverage include general foods or beverages, health foods, health beverages, foods with function claims, foods for specified health uses, health supplements, and foods or beverages for the sick.
- Examples of the health foods, health beverages, the foods with function claims, foods for specified health use, and health supplements can be used in various forms of preparations such as fine granules, tablets, granules, powders, capsules, chewable tablets, dry syrups, syrups, liquids, beverages, soft gel, jelly and liquid foods.
- An example of a preferred form of the agent is a beverage.
- the beverage include tea, coffee, alcoholic beverages, non-alcoholic beverages such as non-alcoholic beer-taste beverages, carbonated beverages, functional beverages, fruit and/or vegetable beverages, dairy beverages, soy milk, flavored water, energy drink, fermented drink such as kombucha, poultry meat extract, poultry meat essence, and protein drink.
- various dosage forms of pharmaceutical or quasi-pharmaceutical products can be provided by, for example, adding a pharmacologically acceptable carrier, an optional additive, or the like to Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
- a carrier, an additive, or the like may be of any pharmacologically acceptable type that can be used in pharmaceutical or quasi-pharmaceutical products. Examples thereof include excipients, binders, disintegrants, lubricants, antioxidants, and colorants. One or more of these can be used.
- Examples of the form of administration (intake) of the pharmaceutical product or quasi-pharmaceutical product include oral administration and parenteral administration (e.g., transdermal, transmucosal, enteral administration, and injection).
- parenteral administration e.g., transdermal, transmucosal, enteral administration, and injection.
- dosage forms for oral administration include liquids, tablets, powders, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, and chewable tablets.
- Examples of dosage forms for parenteral administration include injections, intravenous agents, ointments, lotions, adhesive skin patches, suppositories, nasal agents, and transpulmonary agents (inhalants).
- the pharmaceutical product may be for non-human animals.
- the agent contains Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), and may further contain various types of additives such as diluents, acidulants, antioxidants, stabilizers, preservatives, flavoring or masking agents, emulsifiers, pigments, seasonings, pH adjusters, and nutrient enhancers which are accepted as additives to foods, pharmaceutical products, or the like.
- additives such as diluents, acidulants, antioxidants, stabilizers, preservatives, flavoring or masking agents, emulsifiers, pigments, seasonings, pH adjusters, and nutrient enhancers which are accepted as additives to foods, pharmaceutical products, or the like.
- Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) are added to feed.
- the feed also encompasses feed additives.
- livestock feed for animals such as cows, pigs, chickens, sheep, and horses; feed for small animals such as rabbits, rats, and mice; and pet food for animals such as dogs, cats, and birds.
- the form of a food or beverage, pharmaceutical product, quasi- pharmaceutical product, or feed is not particularly limited, and any commonly used container can be used.
- the beverage may be, for example, a packaged beverage.
- a container includes paper containers such as paper packs; plastic containers such as PET bottles and press through pack sheets (PTP sheets); metal containers such as aluminium cans and steel cans; glass containers such as glass bottles; and wooden containers such as barrels.
- a food or beverage, pharmaceutical product, quasi- pharmaceutical product, or feed may be in bulk in a single container or a single dose in one or more pouches.
- the production method is not limited. Any of these products can be produced by a common method using the four cyclic dipeptides, i.e., Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
- the amount of each of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the agent is not limited, and can be determined depending on the form or the like of the agent.
- the total amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the agent is, for example, preferably 0.0000001 wt% or more, more preferably 0.000001 wt% or more and is preferably 99 wt% or less, more preferably 90 wt% or less.
- the total amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the agent is, for example, preferably 0.0000001 to 99 wt%, more preferably 0.000001 to 90 wt%.
- the amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can be quantitated by a known method such as high performance liquid chromatography (HPLC)and liquid chromatography mass spectroscopy (LCMS).
- the percentage of each cyclic dipeptide in the agent is not limited. The percentage may be the same or different for each cyclic dipeptide.
- the ratio of Cyclo(Phe-Phe) to Cyclo(Gly-Pro), i.e., Cyclo(Gly-Pro)/Cyclo(Phe-Phe) is preferably 0.02 to 450, more preferably 0.5 to 10, still more preferably 0.5 to 6.
- the ratio of Cyclo(Phe-Phe) to Cyclo(His-Pro), i.e., Cyclo(His-Pro)/Cyclo(Phe-Phe) is preferably 0.01 to 200, more preferably 0.1 to 10, still more preferably 0.5 to 3.
- the ratio of Cyclo(Phe-Phe) to Cyclo(Val-Pro), i.e., Cyclo(Val-Pro)/Cyclo(Phe-Phe) is preferably 0.01 to 250, more preferably 0.1 to 10, still more preferably 0.5 to 4.
- the agent is orally fed (orally administered).
- the dose (intake) of the agent is not limited.
- the dose of the agent may be any amount that provides the effect of inhibiting a decline in cognitive function or the effect of ameliorating cognitive dysfunction.
- the dose may be suitably set according to the dosage form, administration method, body weight of a subject, and the like.
- the dose in terms of the total dose of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) is preferably 0.001 mg or more, more preferably 0.01 mg or more, still more preferably 0.1 mg or more, and is preferably 50000 mg or less, more preferably 10000 mg or less, still more preferably 1000 mg or less, per 60 kg body weight per day.
- the oral dose of the agent in terms of the total dose of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) for a human (adult) is preferably 0.001 to 50000 mg, more preferably 0.01 to 10000 mg, still more preferably 0.1 to 1000 mg, per 60 kg body weight per day. Intake or administration of the above amount in one or more portions per day, for example, one to several times (e.g., two to three times) per day, is preferred. In one embodiment, preferably, the above amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) is orally fed or administered to a human. In one embodiment, the agent can be used to feed or administer the above amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to a human per 60 kg body weight per day.
- the agent is fed or administered continuously.
- the above effects are expected to increase by continuous feeding or administration of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
- the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction is continuously fed or administered preferably for at least one week, more preferably for at least four weeks, still more preferably for at least eight weeks.
- a subject to be fed or administered (administration subject) with the agent is not limited.
- the subject is preferably a human or non-human mammal, more preferably a human.
- an administration subject of the agent may be, for example, one who needs or wants to inhibit a decline in cognitive function or ameliorate cognitive dysfunction. Examples of such a subject include those who need or want to inhibit a decline in cognitive function or ameliorate cognitive dysfunction, and those who need or want to prevent or ameliorate an inflammatory condition or disease.
- examples of the administration subject in the present invention include middle-aged and older people. The middle-aged and older people may be those who are 40 years old or older, for example. In one embodiment, the elderly are preferred subjects among the middle-aged and older people.
- the elderly may be those who are 60 years old or older or 65 years old or older.
- the agent may be used on healthy people.
- the agent can be used on healthy people for a purpose such as inhibiting a decline in cognitive function or preventing cognitive dysfunction.
- the agent can be used for subjects with a decline in cognitive function or cognitive dysfunction, or for subjects with conditions or diseases associated with a decline in cognitive function or cognitive dysfunction.
- the agent may be labeled with one or more of function claims.
- Such labels are also referred to as function claims, and the contents of the labels are not limited.
- Examples of such labels include "enhancing cognitive function”, “inhibiting a decline in cognitive function”, “maintaining good cognitive function”, “improving memory”, “inhibiting a decline in memory”, “maintaining good memory”, “improving accuracy of memory”, “preventing memory disorders”, “ameliorating memory disorders”, “maintaining memory that is one domain of cognitive function”, “function suitable for those who are concerned about a decline in memory”, “improving accuracy of memory and/or correctness of judgement that are part of cognitive function”, “improving memory retention or consolidation”, “sustaining cognitive enhancement”, “improving executive function”, “promoting attention and concentration”, “improving learning ability”, “delaying aging-related cognitive decline", “enhancing short-term and long-term memory”, “promoting verbal and visuospatial memory”, and labels or function claims equated to these labels.
- the agent is a food with one or more of the above labels.
- the above labels may be labels indicating use of the agent for obtaining the above functions. These labels may be directly attached to the agent or may be attached to a container or package of the agent.
- the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction can also be referred to as a cognitive function decline inhibitor or a cognitive dysfunction ameliorator.
- the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention can also be used as a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- the present invention also relates to a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, the composition containing Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) as active ingredients.
- the composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention is also simply referred to as the composition of the present invention.
- Embodiments of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) used as active ingredients and amounts thereof in the composition are as described above for the agent.
- the composition of the present invention contains the above active ingredients and may further contain various additives and the like described above.
- composition of the present invention and its preferred embodiments are as described above for the agent.
- the subject to be fed or administered with the composition of the present invention, dose of the composition of the present invention, and their preferred embodiments are as described above for the agent.
- the composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention can inhibit a decline in cognitive function such as memory function or ameliorate cognitive dysfunction.
- a condition or disease that can be prevented or ameliorated by the composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention is as described above for the agent.
- the present invention also encompasses the following method.
- a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction including administering or feeding Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
- the present invention also encompasses the following use. Use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- the method may be a therapeutic or non-therapeutic method.
- the use may be therapeutic or non-therapeutic use.
- the dose, dosage, subject, and the like of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) are as described above for the agent.
- Cyclic dipeptides also known as diketopiperazines (DKPs) including cyclo-phenylalanine-phenylalanine (Cyclo(Phe-Phe), CFF), cyclo-glycine-proline (Cyclo(Gly-Pro), CGP), cyclo-histidine-proline (Cyclo(His-Pro), CHP) and cyclo-valine-proline (Cyclo(Val-Pro), CVP) were bought from Bachem.
- DKPs diketopiperazines
- PLL Poly-L-lysine coated 96-well plates were provided by Corning.
- SIM-A9 murine microglial cells were maintained in DMEM/F12 supplemented with 10% of FBS, 5% of HS, 1% of P/S and 0.5% of dimethyl sulfoxide (DMSO).
- Cells (passage number:14 (P14)) were seeded in a PLL-coated 96-well plate at a cell density of 20,000 cells/well and incubated overnight at 37°C in a humidified gas chamber containing 5% of CO 2 .
- IL-1 ⁇ The Mouse Cytokine Multiplex Assay (Bio-Rad) was used to analyse the cytokines in the culture media. The following 23-plex analyses were performed: IL-1 ⁇ , IL-1 ⁇ , IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17A, keratinocytes-derived chemokine (KC/CXCL1), eotaxin (CCL11), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)- ⁇ , monocyte chemotactic protein 1 (MCP-1; CCL2), macrophage inflammatory protein-1 ⁇ (MIP-1 ⁇ ; CCL3), MIP-1 ⁇ (CCL4), regulated upon activation normal T cell expressed and activated (RANTES) (CCL5)
- Cyclo(Phe-Phe) concentration was 22 ⁇ g/mL
- Cyclo(Gly-Pro) concentration was 71 ⁇ g/mL
- Cyclo(His-Pro) concentration was 28 ⁇ g/mL
- Cyclo(Val-Pro) concentration was 34 ⁇ g/mL.
- the concentration of each cyclic dipeptide in 4DKPs was 22 ⁇ g/mL for Cyclo(Phe-Phe), 71 ⁇ g/mL for Cyclo(Gly-Pro), 28 ⁇ g/mL for Cyclo(His-Pro) and 34 ⁇ g/mL for Cyclo(Val-Pro).
- Cell culture and Treatments For Nitrite assay, cells were plated in a PLL-coated 96-well plate, at 20000 cells/well. Each of four cyclic dipeptides or a combination of four cyclic dipeptides was added to the cells separately and the cells were pre-incubated for 24 hours. After the pre-incubation period, LPS was added at 2.5 ⁇ g/mL for a further 24 hours. Cells were centrifuged at 1,000rpm for 5 min. Supernatant was collected and assayed 48 hours post-plating.
- Nitrite Analysis To determine the amount of nitric oxide (NO) produced, the culture medium collected was incubated with Griess Reagent (Promega) according to manufacturer’s instructions. Nitrite ion (NO 2 - ), a stable derivative of NO, was measured and quantified with a plate reader at 540nm (ref 690nm).
- Cyclo(Phe-Phe) concentration was 22 ⁇ g/mL
- Cyclo(Gly-Pro) concentration was 71 ⁇ g/mL
- Cyclo(His-Pro) concentration was 28 ⁇ g/mL
- Cyclo(Val-Pro) concentration was 34 ⁇ g/mL.
- the concentration of each cyclic dipeptide in 4DKPs was 22 ⁇ g/mL for Cyclo(Phe-Phe), 71 ⁇ g/mL for Cyclo(Gly-Pro), 28 ⁇ g/mL for Cyclo(His-Pro) and 34 ⁇ g/mL for Cyclo(Val-Pro).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Organic Chemistry (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Mycology (AREA)
- Pain & Pain Management (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present invention aims to provide an agent effective for inhibiting a decline in cognitive function such as memory function or ameliorating cognitive dysfunction. The present invention relates to use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the production of an agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
Description
The present invention relates to use of cyclic dipeptides in the production of an agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction. The present invention also relates to a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, and a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
Improvement in cognitive function such as memory function is desired by many people regardless of generation. Recently, an aging-related decline in cognitive function has been a problem in countries where the elderly ratio in the population is high, and search has been made for a component capable of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction through daily intake of the component as a food, beverage, or the like.
For example, Patent Literature 1 discloses an agent containing Cyclo(Gly-Pro) for inhibiting a decline in cognitive function and/or for improving cognitive function. According to the disclosure, oral intake of the agent for inhibiting a decline in cognitive function and/or improving cognitive function by a human can inhibit a decline in attention/concentration, language ability, and visuospatial/constructional ability, and/or can improve these abilities.
The present invention aims to provide an agent effective in inhibiting a decline in cognitive function such as memory function or ameliorating cognitive dysfunction. The present invention also aims to provide a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction. The present invention also aims to provide a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
As a result of extensive studies on the above problems, the present inventors found that combination use of specific cyclic dipeptides significantly increases the effect of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, and thus completed the present invention.
Specifically, the present invention relates to, but is not limited to, use, a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, and a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, for example, which are described as follows.
(1) Use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the production of an agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
(2) The use according to (1) above, wherein the cognitive dysfunction is aging-related cognitive dysfunction.
(3) The use according to (1) or (2) above, wherein the cognitive function includes at least one selected from the group consisting of memory function, executive function, attention, and concentration.
(4) The use according to (3) above, wherein the memory function includes at least one selected from the group consisting of verbal memory function, nonverbal memory function, visuospatial memory function, gist memory function, and working memory function.
(5) The use according to any one of (1) to (4) above,
wherein the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of inflammation in the brain.
(6) The use according to (5) above,
wherein the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit the inflammation in the brain by inhibition of the production of nitric oxide.
(7) The use according to any one of (1) to (5) above, wherein the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of the production of tumor necrosis factor-α (TNF-α).
(8) The use according to any one of (1) to (7) above, wherein the agent is for oral administration.
(9) The use according to any one of (1) to (8) above, wherein the agent is a food or beverage, or pharmaceutical product.
(10) The use according to any one of (1) to (9) above, wherein the agent is labeled with one or more function claims selected from the group consisting of "enhancing cognitive function", "inhibiting a decline in cognitive function", "maintaining good cognitive function", "improving memory", "inhibiting a decline in memory", "maintaining good memory", "improving accuracy of memory", "preventing memory disorders", "ameliorating memory disorders", "maintaining memory that is one domain of cognitive function", "function suitable for those who are concerned about a decline in memory", "improving accuracy of memory and/or correctness of judgement that are part of cognitive function", "improving memory retention or consolidation", "sustaining cognitive enhancement", "improving executive function", "promoting attention and concentration", "improving learning ability", "delaying aging-related cognitive decline", "enhancing short-term and long-term memory" and "promoting verbal and visuospatial memory".
(11) Use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
(12) A composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, containing: Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) as active ingredients.
(13) A method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, including: administering or feeding Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
(1) Use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the production of an agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
(2) The use according to (1) above, wherein the cognitive dysfunction is aging-related cognitive dysfunction.
(3) The use according to (1) or (2) above, wherein the cognitive function includes at least one selected from the group consisting of memory function, executive function, attention, and concentration.
(4) The use according to (3) above, wherein the memory function includes at least one selected from the group consisting of verbal memory function, nonverbal memory function, visuospatial memory function, gist memory function, and working memory function.
(5) The use according to any one of (1) to (4) above,
wherein the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of inflammation in the brain.
(6) The use according to (5) above,
wherein the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit the inflammation in the brain by inhibition of the production of nitric oxide.
(7) The use according to any one of (1) to (5) above, wherein the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of the production of tumor necrosis factor-α (TNF-α).
(8) The use according to any one of (1) to (7) above, wherein the agent is for oral administration.
(9) The use according to any one of (1) to (8) above, wherein the agent is a food or beverage, or pharmaceutical product.
(10) The use according to any one of (1) to (9) above, wherein the agent is labeled with one or more function claims selected from the group consisting of "enhancing cognitive function", "inhibiting a decline in cognitive function", "maintaining good cognitive function", "improving memory", "inhibiting a decline in memory", "maintaining good memory", "improving accuracy of memory", "preventing memory disorders", "ameliorating memory disorders", "maintaining memory that is one domain of cognitive function", "function suitable for those who are concerned about a decline in memory", "improving accuracy of memory and/or correctness of judgement that are part of cognitive function", "improving memory retention or consolidation", "sustaining cognitive enhancement", "improving executive function", "promoting attention and concentration", "improving learning ability", "delaying aging-related cognitive decline", "enhancing short-term and long-term memory" and "promoting verbal and visuospatial memory".
(11) Use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
(12) A composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, containing: Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) as active ingredients.
(13) A method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, including: administering or feeding Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
The present invention provides an agent effective in inhibiting a decline in cognitive function such as memory function or ameliorating cognitive dysfunction. The present invention also provides a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction and the like. The agent and the composition of the present invention can be used as foods or beverages, pharmaceutical products, or the like for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction. Cyclic dipeptides are ingestible as foods, beverages, pharmaceutical products, or the like by humans, and are advantageously highly safe. The present invention also provides a method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
The present invention relates to use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the production of an agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction. A combination use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) shows excellent effects of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can be used as active ingredients of the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
The agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction usually contains Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) as active ingredients.
Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can be used as active ingredients of the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
The agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction usually contains Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) as active ingredients.
All of the Cyclo(Phe-Phe) (cyclo-phenylalanyl-phenylalanine), Cyclo(Gly-Pro) (cyclo-glycyl-proline), Cyclo(His-Pro) (cyclo-histidyl-proline), and Cyclo(Val-Pro) (cyclo-valyl-proline) are cyclic dipeptides. Herein, the term "cyclic dipeptide" refers to a compound whose structural units are amino acids and which has a diketopiperazine structure produced by dehydration condensation of an amino group of an amino acid at the N-terminal side and a carboxy group of an amino acid at the C-terminal side. Herein, the description order of amino acids in a cyclic dipeptide is not limited as long as the amino acid structure is unchanged. For example, Cyclo(Gly-Pro) and Cyclo(Pro-Gly) (cyclo-prolyl-glycine) represent an identical cyclic dipeptide.
Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro) and Cyclo(Val-Pro) can be used in the form of a salt with an inorganic acid or an organic acid or a salt with an inorganic base or an organic base in the present invention. Such an acid or a base can be selected based on the application of the salt. In view of application to foods, beverages, and pharmaceutical products, the following dietary or pharmaceutically acceptable salts are preferred. Examples of the inorganic acid salt include hydrochloride, nitrate, sulfate, methanesulfonate, and p-toluenesulfonate. Examples of the organic acid salt include salts with dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, and salts with monocarboxylic acids such as acetic acid, propionic acid, and butyric acid. Examples of the inorganic base include hydroxides, carbonates, and bicarbonates of sodium, lithium, calcium, magnesium, and aluminium and ammonia. Examples of the salt with the organic base include mono-, di-, or tri-alkylamine salts such as salts of methylamine, dimethylamine, and triethylamine, mono-, di-, or tri-hydroxyalkylamine salts, guanidine salt, and N-methylglucosamine salt.
In the present invention, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) may be derived from extracts of natural products such as an extract obtained by heat treatment of natural product or hydrolyzed protein, or may be artificially synthesized products. When these cyclic dipeptides are derived from the extracts of natural products, they can be obtained, for example, by heating protein or protein hydrolysates such as plant protein hydrolysates, poultry protein hydrolysates or collagen hydrolysates in water.
Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) may be used in the form of protein hydrolysates containing these cyclic dipeptides, or may be used in the form of concentrates, dry powder, or purified products thereof. Cyclic dipeptides are ingestible as foods or beverages and are highly safe.
In the present invention, the above protein hydrolysates or heat-treated product thereof can be used to add Cyclo (Phe-Phe), Cyclo (Gly-Pro), Cyclo (His-Pro) and Cyclo (Val-Pro) to the agent or composition.
Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) may be used in the form of protein hydrolysates containing these cyclic dipeptides, or may be used in the form of concentrates, dry powder, or purified products thereof. Cyclic dipeptides are ingestible as foods or beverages and are highly safe.
In the present invention, the above protein hydrolysates or heat-treated product thereof can be used to add Cyclo (Phe-Phe), Cyclo (Gly-Pro), Cyclo (His-Pro) and Cyclo (Val-Pro) to the agent or composition.
In the present invention, the cognitive function refers to the brain function such as memory function, learning ability, memory consolidation, executive function, attention (attention function), and concentration. The cognitive dysfunction means partial or entire failure of the cognitive function.
In the present invention, the phrase "inhibiting a decline in cognitive function" encompasses maintaining cognitive function, slowing down the speed of decline in cognitive function, stopping decline in cognitive function, and the like. The phrase "ameliorating cognitive dysfunction" encompasses alleviating (moderating) the degree of cognitive dysfunction, recovering cognitive function, improving cognitive function, and the like. The phrase "inhibiting a decline in cognitive function or ameliorating cognitive dysfunction" encompasses inhibiting a decline in part of cognitive function or ameliorating part of cognitive dysfunction. The term "recovering" encompasses at least partial recovering.
Examples of causes of the decline in cognitive function or cognitive dysfunction include aging; neurodegenerative diseases such as Alzheimer's disease, Pick's disease, and diffuse Lewy body disease; brain diseases such as cerebral infarction, cerebral hemorrhage, chronic subdural hematoma, brain tumor, encephalitis, and normal pressure hydrocephalus; dementia such as vascular dementia and frontotemporal dementia; and Creutzfeldt-Jakob disease.
In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to ameliorate aging-related cognitive dysfunction. The aging-related cognitive dysfunction may be aging-related cognitive dysfunction among middle-aged and older people. The middle-aged and older people include the elderly.
In the present invention, the phrase "inhibiting a decline in cognitive function" encompasses maintaining cognitive function, slowing down the speed of decline in cognitive function, stopping decline in cognitive function, and the like. The phrase "ameliorating cognitive dysfunction" encompasses alleviating (moderating) the degree of cognitive dysfunction, recovering cognitive function, improving cognitive function, and the like. The phrase "inhibiting a decline in cognitive function or ameliorating cognitive dysfunction" encompasses inhibiting a decline in part of cognitive function or ameliorating part of cognitive dysfunction. The term "recovering" encompasses at least partial recovering.
Examples of causes of the decline in cognitive function or cognitive dysfunction include aging; neurodegenerative diseases such as Alzheimer's disease, Pick's disease, and diffuse Lewy body disease; brain diseases such as cerebral infarction, cerebral hemorrhage, chronic subdural hematoma, brain tumor, encephalitis, and normal pressure hydrocephalus; dementia such as vascular dementia and frontotemporal dementia; and Creutzfeldt-Jakob disease.
In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to ameliorate aging-related cognitive dysfunction. The aging-related cognitive dysfunction may be aging-related cognitive dysfunction among middle-aged and older people. The middle-aged and older people include the elderly.
In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to inhibit a decline in cognitive function or ameliorate cognitive dysfunction, the cognitive function being at least one selected from the group consisting of memory function, executive function, attention, and concentration.
The memory function is a function for retaining information from past experiences and retrieving the information for use at a later time. The memory function is classified into, for example, verbal memory function, nonverbal memory function, visuospatial memory function, gist memory function, and working memory function.
The executive function is a function for making decision, formulating and carrying out plans to achieve goals, and is an essential function for people to behave socially, independently, and creatively. The executive function compares various kinds of information such as visual, auditory, and olfactory information to information from past experiences and coordinate the information in the frontal lobe.
The attention is a function for selecting information from a large amount of information. It is an information selective processing function for selectively processing necessary information by not assigning processing resources to unnecessary information in order to effectively use limited processing resources in the brain.
The concentration is a function for investing mental effort or focusing effectively on the task at hand while ignoring distractions in any given situation.
In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to inhibit a decline in memory function or improve memory function, and can be more suitably used to inhibit a decline in verbal memory function, nonverbal memory function, visuospatial memory function, gist memory function, and working memory function, or improve these functions.
The concentration is a function for investing mental effort or focusing effectively on the task at hand while ignoring distractions in any given situation.
In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to inhibit a decline in memory function or improve memory function, and can be more suitably used to inhibit a decline in verbal memory function, nonverbal memory function, visuospatial memory function, gist memory function, and working memory function, or improve these functions.
As described in the later-described examples, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) when used in combination exhibit an excellent action to inhibit the production of nitric oxide (NO). The effect of inhibiting the production of NO, which is obtainable by the combination of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), is a significant effect that cannot be predicted from the effect of inhibiting the production of NO which is obtainable when each of these cyclic dipeptides is used alone.
For example, in an aging-related inflammatory condition, NO is attached to superoxide to form peroxynitrite (ONOO-). Peroxynitrite in the brain is known to cause, for example, inflammation in the brain such as oxidative stress in the brain and neuroinflammation. Inflammation in the brain is considered to be one of the causes of a decline in cognitive function in Alzheimer's disease and the like. Thus, inhibition of the production of peroxynitrite by inhibition of the production of NO is considered to inhibit a decline in cognitive function.
Intake or administration of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can inhibit the production of NO and in turn can inhibit inflammation in the brain. Inhibition of inflammation in the brain can inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
The action of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to inhibit the production of NO is observed in, for example, microglial cells and the like. Microglial cells are a type of glial cells in the central nervous system, and are considered to be the major central immunocompetent cells. An increase in the production of NO in microglial cells is known to relate to a decline in cognitive function. Inhibition of the production of NO in microglial cells inhibits inflammation in the brain, which in turn can inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) , or an agent containing these cyclic dipeptides can be used to inhibit inflammation in the brain so to as inhibit a decline in cognitive function or ameliorate cognitive dysfunction. In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used, for example, to inhibit a decline in cognitive function associated with inflammation in the brain or ameliorate cognitive dysfunction associated with inflammation in the brain. Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used to inhibit inflammation in the brain by inhibition of the production of NO so as to inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
Intake or administration of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can inhibit the production of NO and in turn can inhibit inflammation in the brain. Inhibition of inflammation in the brain can inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
The action of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to inhibit the production of NO is observed in, for example, microglial cells and the like. Microglial cells are a type of glial cells in the central nervous system, and are considered to be the major central immunocompetent cells. An increase in the production of NO in microglial cells is known to relate to a decline in cognitive function. Inhibition of the production of NO in microglial cells inhibits inflammation in the brain, which in turn can inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) , or an agent containing these cyclic dipeptides can be used to inhibit inflammation in the brain so to as inhibit a decline in cognitive function or ameliorate cognitive dysfunction. In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used, for example, to inhibit a decline in cognitive function associated with inflammation in the brain or ameliorate cognitive dysfunction associated with inflammation in the brain. Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used to inhibit inflammation in the brain by inhibition of the production of NO so as to inhibit a decline in cognitive function or ameliorate cognitive dysfunction.
As described in the later-described examples, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) when used in combination have an excellent action to inhibit the production of inflammatory markers. Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can be suitably used to inhibit the production of particularly tumor necrosis factor-α (TNF-α) among inflammatory markers.
The effect of inhibiting the production of TNF-α, which is obtainable by the combination of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), is a significant effect that cannot be predicted from the effect of inhibiting the production of inflammatory markers which is obtainable when each of these cyclic dipeptides is used alone.
The action of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to inhibit the production of inflammatory markers is observed in, for example, microglial cells. An increase in the production of TNF-α is known to relate to a decline in cognitive function. Preferably, inflammation in the brain is inhibited by inhibition of the production of TNF-α in microglial cells, which in turn can inhibit a decline in cognitive function or ameliorate cognitive dysfunction. Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of the production of TNF-α, and can be suitably used for such purposes.
The effect of inhibiting the production of TNF-α, which is obtainable by the combination of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), is a significant effect that cannot be predicted from the effect of inhibiting the production of inflammatory markers which is obtainable when each of these cyclic dipeptides is used alone.
The action of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to inhibit the production of inflammatory markers is observed in, for example, microglial cells. An increase in the production of TNF-α is known to relate to a decline in cognitive function. Preferably, inflammation in the brain is inhibited by inhibition of the production of TNF-α in microglial cells, which in turn can inhibit a decline in cognitive function or ameliorate cognitive dysfunction. Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of the production of TNF-α, and can be suitably used for such purposes.
Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used to prevent or ameliorate a condition or disease that can be prevented or ameliorated by inhibition of a decline in cognitive function or amelioration of cognitive dysfunction. Such a condition or disease may be a condition or disease that shows a decline in cognitive function, or a condition associated with a decline in cognitive function. Examples thereof include a decline in memory, memory disorders (forgetfulness), aphasia (inability to formulate words), apraxia, agnosia (e.g., getting lost in a familiar place), a decline in verbal and non-verbal learning, a decline in auditory and visual processing, a decline in problem solving, a decline in executive function, executive dysfunction (inability to formulate and carry out plans), a decline in concentration, a decline in attention, a decline in judgement, a decline in spatial awareness, a decline in cognitive flexibility, and a decline in information processing speed. In particular, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to prevent or ameliorate a decline in memory, memory disorders, aphasia, apraxia, executive dysfunction, a decline in executive function, a decline in concentration, a decline in attention, and the like. In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be suitably used to prevent or ameliorate an aging-related decline in memory, memory disorders, aphasia, apraxia, verbal learning, a decline in executive function, a decline in concentration, a decline in attention, and the like. In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used to prevent or ameliorate the above conditions or diseases by inhibition of the production of NO. In one embodiment, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), or an agent containing these cyclic dipeptides can be used to prevent or ameliorate the above conditions or diseases by inhibition of the production of TNF-α.
Herein, the expression "prevention of a condition or disease" encompasses preventing the onset of a condition or disease, delaying the onset of a condition or disease, reducing the incidence, reducing the onset risk, and the like. The expression "amelioration of a condition or disease" encompasses helping a subject recover from a condition or disease, alleviating a symptom of a condition or disease, changing a symptom of a condition or disease for the better, delaying or preventing the progress of a condition or disease, and the like.
Herein, the expression "prevention of a condition or disease" encompasses preventing the onset of a condition or disease, delaying the onset of a condition or disease, reducing the incidence, reducing the onset risk, and the like. The expression "amelioration of a condition or disease" encompasses helping a subject recover from a condition or disease, alleviating a symptom of a condition or disease, changing a symptom of a condition or disease for the better, delaying or preventing the progress of a condition or disease, and the like.
In the present invention, the agent containing Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) is applicable for either therapeutic use (medical use) or non-therapeutic use (non-medical use). The "non-therapeutic" is a concept that does not include medical activities, i.e., a concept that does not include surgery, therapy, or diagnosis of humans.
The agent can be provided directly as a composition, or can be provided as a composition containing the agent.
The agent can be provided directly as a composition, or can be provided as a composition containing the agent.
In the present invention, the agent may be either for oral administration or parenteral administration. Preferably, the agent is for oral administration. The agent can be provided, for example, as a food or beverage, pharmaceutical product, quasi-pharmaceutical product, or feed. A food or beverage, or pharmaceutical product is preferred. The agent can be used by being added to a food or beverage, pharmaceutical product, quasi-pharmaceutical product, feed, or the like.
For example, when the agent is provided as a food or beverage, components usable in a food or beverage (e.g., food or beverage materials and optional food or beverage additives) can be added to Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to provide various foods or beverages. Non-limiting examples of the food or beverage include general foods or beverages, health foods, health beverages, foods with function claims, foods for specified health uses, health supplements, and foods or beverages for the sick. Examples of the health foods, health beverages, the foods with function claims, foods for specified health use, and health supplements can be used in various forms of preparations such as fine granules, tablets, granules, powders, capsules, chewable tablets, dry syrups, syrups, liquids, beverages, soft gel, jelly and liquid foods.
For example, when the agent is provided as a food or beverage, components usable in a food or beverage (e.g., food or beverage materials and optional food or beverage additives) can be added to Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to provide various foods or beverages. Non-limiting examples of the food or beverage include general foods or beverages, health foods, health beverages, foods with function claims, foods for specified health uses, health supplements, and foods or beverages for the sick. Examples of the health foods, health beverages, the foods with function claims, foods for specified health use, and health supplements can be used in various forms of preparations such as fine granules, tablets, granules, powders, capsules, chewable tablets, dry syrups, syrups, liquids, beverages, soft gel, jelly and liquid foods.
An example of a preferred form of the agent is a beverage.
Non-limiting examples of the beverage include tea, coffee, alcoholic beverages, non-alcoholic beverages such as non-alcoholic beer-taste beverages, carbonated beverages, functional beverages, fruit and/or vegetable beverages, dairy beverages, soy milk, flavored water, energy drink, fermented drink such as kombucha, poultry meat extract, poultry meat essence, and protein drink.
Non-limiting examples of the beverage include tea, coffee, alcoholic beverages, non-alcoholic beverages such as non-alcoholic beer-taste beverages, carbonated beverages, functional beverages, fruit and/or vegetable beverages, dairy beverages, soy milk, flavored water, energy drink, fermented drink such as kombucha, poultry meat extract, poultry meat essence, and protein drink.
When the agent is provided as a pharmaceutical product or a quasi-pharmaceutical product, various dosage forms of pharmaceutical or quasi-pharmaceutical products can be provided by, for example, adding a pharmacologically acceptable carrier, an optional additive, or the like to Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro). Such a carrier, an additive, or the like may be of any pharmacologically acceptable type that can be used in pharmaceutical or quasi-pharmaceutical products. Examples thereof include excipients, binders, disintegrants, lubricants, antioxidants, and colorants. One or more of these can be used. Examples of the form of administration (intake) of the pharmaceutical product or quasi-pharmaceutical product include oral administration and parenteral administration (e.g., transdermal, transmucosal, enteral administration, and injection). When the agent is provided as a pharmaceutical product or quasi-pharmaceutical product, a pharmaceutical product for oral administration or a quasi-pharmaceutical product for oral administration is preferred. Examples of dosage forms for oral administration include liquids, tablets, powders, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, and chewable tablets. Examples of dosage forms for parenteral administration include injections, intravenous agents, ointments, lotions, adhesive skin patches, suppositories, nasal agents, and transpulmonary agents (inhalants). The pharmaceutical product may be for non-human animals.
The agent contains Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro), and may further contain various types of additives such as diluents, acidulants, antioxidants, stabilizers, preservatives, flavoring or masking agents, emulsifiers, pigments, seasonings, pH adjusters, and nutrient enhancers which are accepted as additives to foods, pharmaceutical products, or the like.
When the agent is provided as feed, Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) are added to feed. The feed also encompasses feed additives. Examples of the feed include livestock feed for animals such as cows, pigs, chickens, sheep, and horses; feed for small animals such as rabbits, rats, and mice; and pet food for animals such as dogs, cats, and birds.
The form of a food or beverage, pharmaceutical product, quasi- pharmaceutical product, or feed is not particularly limited, and any commonly used container can be used. The beverage may be, for example, a packaged beverage. Such a container includes paper containers such as paper packs; plastic containers such as PET bottles and press through pack sheets (PTP sheets); metal containers such as aluminium cans and steel cans; glass containers such as glass bottles; and wooden containers such as barrels.
A food or beverage, pharmaceutical product, quasi- pharmaceutical product, or feed may be in bulk in a single container or a single dose in one or more pouches.
A food or beverage, pharmaceutical product, quasi- pharmaceutical product, or feed may be in bulk in a single container or a single dose in one or more pouches.
When the agent is provided as, for example, a food or beverage, pharmaceutical product, quasi-pharmaceutical product, or feed, the production method is not limited. Any of these products can be produced by a common method using the four cyclic dipeptides, i.e., Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
In the present invention, the amount of each of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the agent is not limited, and can be determined depending on the form or the like of the agent.
In one embodiment, the total amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the agent is, for example, preferably 0.0000001 wt% or more, more preferably 0.000001 wt% or more and is preferably 99 wt% or less, more preferably 90 wt% or less. In one embodiment, the total amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the agent is, for example, preferably 0.0000001 to 99 wt%, more preferably 0.000001 to 90 wt%.
The amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can be quantitated by a known method such as high performance liquid chromatography (HPLC)and liquid chromatography mass spectroscopy (LCMS).
In one embodiment, the total amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the agent is, for example, preferably 0.0000001 wt% or more, more preferably 0.000001 wt% or more and is preferably 99 wt% or less, more preferably 90 wt% or less. In one embodiment, the total amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the agent is, for example, preferably 0.0000001 to 99 wt%, more preferably 0.000001 to 90 wt%.
The amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) can be quantitated by a known method such as high performance liquid chromatography (HPLC)and liquid chromatography mass spectroscopy (LCMS).
In the present invention, the percentage of each cyclic dipeptide in the agent is not limited. The percentage may be the same or different for each cyclic dipeptide.
In the present invention, the ratio of Cyclo(Phe-Phe) to Cyclo(Gly-Pro), i.e., Cyclo(Gly-Pro)/Cyclo(Phe-Phe) is preferably 0.02 to 450, more preferably 0.5 to 10, still more preferably 0.5 to 6. The ratio of Cyclo(Phe-Phe) to Cyclo(His-Pro), i.e., Cyclo(His-Pro)/Cyclo(Phe-Phe) is preferably 0.01 to 200, more preferably 0.1 to 10, still more preferably 0.5 to 3. The ratio of Cyclo(Phe-Phe) to Cyclo(Val-Pro), i.e., Cyclo(Val-Pro)/Cyclo(Phe-Phe) is preferably 0.01 to 250, more preferably 0.1 to 10, still more preferably 0.5 to 4.
In the present invention, the ratio of Cyclo(Phe-Phe) to Cyclo(Gly-Pro), i.e., Cyclo(Gly-Pro)/Cyclo(Phe-Phe) is preferably 0.02 to 450, more preferably 0.5 to 10, still more preferably 0.5 to 6. The ratio of Cyclo(Phe-Phe) to Cyclo(His-Pro), i.e., Cyclo(His-Pro)/Cyclo(Phe-Phe) is preferably 0.01 to 200, more preferably 0.1 to 10, still more preferably 0.5 to 3. The ratio of Cyclo(Phe-Phe) to Cyclo(Val-Pro), i.e., Cyclo(Val-Pro)/Cyclo(Phe-Phe) is preferably 0.01 to 250, more preferably 0.1 to 10, still more preferably 0.5 to 4.
In the present invention, preferably, the agent is orally fed (orally administered). The dose (intake) of the agent is not limited. The dose of the agent may be any amount that provides the effect of inhibiting a decline in cognitive function or the effect of ameliorating cognitive dysfunction. The dose may be suitably set according to the dosage form, administration method, body weight of a subject, and the like.
In one embodiment, when the agent is orally fed or administered to a human (adult), the dose in terms of the total dose of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) is preferably 0.001 mg or more, more preferably 0.01 mg or more, still more preferably 0.1 mg or more, and is preferably 50000 mg or less, more preferably 10000 mg or less, still more preferably 1000 mg or less, per 60 kg body weight per day. In one embodiment, the oral dose of the agent in terms of the total dose of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) for a human (adult) is preferably 0.001 to 50000 mg, more preferably 0.01 to 10000 mg, still more preferably 0.1 to 1000 mg, per 60 kg body weight per day. Intake or administration of the above amount in one or more portions per day, for example, one to several times (e.g., two to three times) per day, is preferred. In one embodiment, preferably, the above amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) is orally fed or administered to a human. In one embodiment, the agent can be used to feed or administer the above amount of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) to a human per 60 kg body weight per day.
In the present invention, preferably, the agent is fed or administered continuously. The above effects are expected to increase by continuous feeding or administration of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro). In one embodiment, the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction is continuously fed or administered preferably for at least one week, more preferably for at least four weeks, still more preferably for at least eight weeks.
In the present invention, a subject to be fed or administered (administration subject) with the agent is not limited. The subject is preferably a human or non-human mammal, more preferably a human.
In one embodiment, an administration subject of the agent may be, for example, one who needs or wants to inhibit a decline in cognitive function or ameliorate cognitive dysfunction. Examples of such a subject include those who need or want to inhibit a decline in cognitive function or ameliorate cognitive dysfunction, and those who need or want to prevent or ameliorate an inflammatory condition or disease. In one embodiment, examples of the administration subject in the present invention include middle-aged and older people. The middle-aged and older people may be those who are 40 years old or older, for example. In one embodiment, the elderly are preferred subjects among the middle-aged and older people. The elderly may be those who are 60 years old or older or 65 years old or older. The agent may be used on healthy people. For example, the agent can be used on healthy people for a purpose such as inhibiting a decline in cognitive function or preventing cognitive dysfunction. The agent can be used for subjects with a decline in cognitive function or cognitive dysfunction, or for subjects with conditions or diseases associated with a decline in cognitive function or cognitive dysfunction.
In one embodiment, an administration subject of the agent may be, for example, one who needs or wants to inhibit a decline in cognitive function or ameliorate cognitive dysfunction. Examples of such a subject include those who need or want to inhibit a decline in cognitive function or ameliorate cognitive dysfunction, and those who need or want to prevent or ameliorate an inflammatory condition or disease. In one embodiment, examples of the administration subject in the present invention include middle-aged and older people. The middle-aged and older people may be those who are 40 years old or older, for example. In one embodiment, the elderly are preferred subjects among the middle-aged and older people. The elderly may be those who are 60 years old or older or 65 years old or older. The agent may be used on healthy people. For example, the agent can be used on healthy people for a purpose such as inhibiting a decline in cognitive function or preventing cognitive dysfunction. The agent can be used for subjects with a decline in cognitive function or cognitive dysfunction, or for subjects with conditions or diseases associated with a decline in cognitive function or cognitive dysfunction.
The agent may be labeled with one or more of function claims. Such labels are also referred to as function claims, and the contents of the labels are not limited. Examples of such labels include "enhancing cognitive function", "inhibiting a decline in cognitive function", "maintaining good cognitive function", "improving memory", "inhibiting a decline in memory", "maintaining good memory", "improving accuracy of memory", "preventing memory disorders", "ameliorating memory disorders", "maintaining memory that is one domain of cognitive function", "function suitable for those who are concerned about a decline in memory", "improving accuracy of memory and/or correctness of judgement that are part of cognitive function", "improving memory retention or consolidation", "sustaining cognitive enhancement", "improving executive function", "promoting attention and concentration", "improving learning ability", "delaying aging-related cognitive decline", "enhancing short-term and long-term memory", "promoting verbal and visuospatial memory", and labels or function claims equated to these labels.
In one embodiment of the present invention, preferably, the agent is a food with one or more of the above labels. The above labels may be labels indicating use of the agent for obtaining the above functions. These labels may be directly attached to the agent or may be attached to a container or package of the agent.
In one embodiment of the present invention, preferably, the agent is a food with one or more of the above labels. The above labels may be labels indicating use of the agent for obtaining the above functions. These labels may be directly attached to the agent or may be attached to a container or package of the agent.
In one embodiment, the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction can also be referred to as a cognitive function decline inhibitor or a cognitive dysfunction ameliorator.
In one embodiment, the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention can also be used as a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
In one embodiment, the agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention can also be used as a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
The present invention also relates to a composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, the composition containing Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) as active ingredients. The composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention is also simply referred to as the composition of the present invention.
Embodiments of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) used as active ingredients and amounts thereof in the composition are as described above for the agent. The composition of the present invention contains the above active ingredients and may further contain various additives and the like described above.
The form of the composition of the present invention and its preferred embodiments are as described above for the agent. The subject to be fed or administered with the composition of the present invention, dose of the composition of the present invention, and their preferred embodiments are as described above for the agent. The composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention can inhibit a decline in cognitive function such as memory function or ameliorate cognitive dysfunction. A condition or disease that can be prevented or ameliorated by the composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention is as described above for the agent.
Embodiments of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) used as active ingredients and amounts thereof in the composition are as described above for the agent. The composition of the present invention contains the above active ingredients and may further contain various additives and the like described above.
The form of the composition of the present invention and its preferred embodiments are as described above for the agent. The subject to be fed or administered with the composition of the present invention, dose of the composition of the present invention, and their preferred embodiments are as described above for the agent. The composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention can inhibit a decline in cognitive function such as memory function or ameliorate cognitive dysfunction. A condition or disease that can be prevented or ameliorated by the composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction of the present invention is as described above for the agent.
The present invention also encompasses the following method.
A method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, the method including administering or feeding Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
The present invention also encompasses the following use.
Use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
The method may be a therapeutic or non-therapeutic method. The use may be therapeutic or non-therapeutic use. The dose, dosage, subject, and the like of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) are as described above for the agent.
A method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, the method including administering or feeding Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
The present invention also encompasses the following use.
Use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
The method may be a therapeutic or non-therapeutic method. The use may be therapeutic or non-therapeutic use. The dose, dosage, subject, and the like of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) are as described above for the agent.
Hereinafter, the present invention is described in more detail with reference to examples, but these examples are not intended to limit the scope of the present invention.
<Evaluation method of anti-inflammatory activity>
In Examples and Comparative Examples, the effect of inhibiting the production of inflammatory markers was evaluated by the following method.
In Examples and Comparative Examples, the effect of inhibiting the production of inflammatory markers was evaluated by the following method.
(Reagents)
Gibco Dulbecco’s Modified Eagle’s Medium:Nutrient Mixture F-12 Ham 1:1 (DMEM/F12, Cat. #D6421), fetal bovine serum (FBS, Cat. #10500), horse serum (HS, Cat. #26050088) and Penicillin/Streptomycin (P/S, Cat. #15070063) were obtained from ThermoFischer Scientific.
Lipopolysaccharide O111:B4 (LPS, Cat. #LPS25) was purchased from Sigma-Aldrich.
Cyclic dipeptides also known as diketopiperazines (DKPs) including cyclo-phenylalanine-phenylalanine (Cyclo(Phe-Phe), CFF), cyclo-glycine-proline (Cyclo(Gly-Pro), CGP), cyclo-histidine-proline (Cyclo(His-Pro), CHP) and cyclo-valine-proline (Cyclo(Val-Pro), CVP) were bought from Bachem.
Poly-L-lysine (PLL) coated 96-well plates were provided by Corning.
Gibco Dulbecco’s Modified Eagle’s Medium:Nutrient Mixture F-12 Ham 1:1 (DMEM/F12, Cat. #D6421), fetal bovine serum (FBS, Cat. #10500), horse serum (HS, Cat. #26050088) and Penicillin/Streptomycin (P/S, Cat. #15070063) were obtained from ThermoFischer Scientific.
Lipopolysaccharide O111:B4 (LPS, Cat. #LPS25) was purchased from Sigma-Aldrich.
Cyclic dipeptides also known as diketopiperazines (DKPs) including cyclo-phenylalanine-phenylalanine (Cyclo(Phe-Phe), CFF), cyclo-glycine-proline (Cyclo(Gly-Pro), CGP), cyclo-histidine-proline (Cyclo(His-Pro), CHP) and cyclo-valine-proline (Cyclo(Val-Pro), CVP) were bought from Bachem.
Poly-L-lysine (PLL) coated 96-well plates were provided by Corning.
(Cell culture and Treatments)
SIM-A9 murine microglial cells (ATCC) were maintained in DMEM/F12 supplemented with 10% of FBS, 5% of HS, 1% of P/S and 0.5% of dimethyl sulfoxide (DMSO). Cells (passage number:14 (P14)) were seeded in a PLL-coated 96-well plate at a cell density of 20,000 cells/well and incubated overnight at 37°C in a humidified gas chamber containing 5% of CO2. Each of 22 μg/mL of Cyclo(Phe-Phe), 71 μg/mL of Cyclo(Gly-Pro), 28 μg/mL of Cyclo(His-Pro), 34 μg/mL of Cyclo(Val-Pro) or a combination of four cyclic dipeptides was added to the chondrocytes separately and the chondrocytes were pre-treated for 24 hours prior to induction with 100 ng/mL of LPS in the presence of the treatment in serum-free medium for another 24 hours.
Cells were centrifuged at 1100 g for 5 min and the supernatant was then used for cytokine analysis.
SIM-A9 murine microglial cells (ATCC) were maintained in DMEM/F12 supplemented with 10% of FBS, 5% of HS, 1% of P/S and 0.5% of dimethyl sulfoxide (DMSO). Cells (passage number:14 (P14)) were seeded in a PLL-coated 96-well plate at a cell density of 20,000 cells/well and incubated overnight at 37°C in a humidified gas chamber containing 5% of CO2. Each of 22 μg/mL of Cyclo(Phe-Phe), 71 μg/mL of Cyclo(Gly-Pro), 28 μg/mL of Cyclo(His-Pro), 34 μg/mL of Cyclo(Val-Pro) or a combination of four cyclic dipeptides was added to the chondrocytes separately and the chondrocytes were pre-treated for 24 hours prior to induction with 100 ng/mL of LPS in the presence of the treatment in serum-free medium for another 24 hours.
Cells were centrifuged at 1100 g for 5 min and the supernatant was then used for cytokine analysis.
(Multiplex cytokine analysis)
The Mouse Cytokine Multiplex Assay (Bio-Rad) was used to analyse the cytokines in the culture media. The following 23-plex analyses were performed: IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17A, keratinocytes-derived chemokine (KC/CXCL1), eotaxin (CCL11), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, monocyte chemotactic protein 1 (MCP-1; CCL2), macrophage inflammatory protein-1α (MIP-1α; CCL3), MIP-1β (CCL4), regulated upon activation normal T cell expressed and activated (RANTES) (CCL5) and TNF-α. Multiplex assays were carried out according to the manufacturers’ instructions and run on the Luminex xPONENT for MAGPIX platform. Bio-Plex Manager version 6.0 was used for data processing. Cytokine and chemokine concentrations were calculated by reference to the standard curve. The sensitivity of the multiplex kit was <5 pg/mL.
The Mouse Cytokine Multiplex Assay (Bio-Rad) was used to analyse the cytokines in the culture media. The following 23-plex analyses were performed: IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17A, keratinocytes-derived chemokine (KC/CXCL1), eotaxin (CCL11), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, monocyte chemotactic protein 1 (MCP-1; CCL2), macrophage inflammatory protein-1α (MIP-1α; CCL3), MIP-1β (CCL4), regulated upon activation normal T cell expressed and activated (RANTES) (CCL5) and TNF-α. Multiplex assays were carried out according to the manufacturers’ instructions and run on the Luminex xPONENT for MAGPIX platform. Bio-Plex Manager version 6.0 was used for data processing. Cytokine and chemokine concentrations were calculated by reference to the standard curve. The sensitivity of the multiplex kit was <5 pg/mL.
(Statistical analyses)
Statistical analysis was conducted using GraphPad Prism version 5.0 (San Diego). All results are expressed as mean ± standard deviation. Statistical analysis was performed by analysis of variance (ANOVA) followed by posthoc Tukey’s multiple comparison test. Data was considered to be significant when P-value, p < 0.05.
Statistical analysis was conducted using GraphPad Prism version 5.0 (San Diego). All results are expressed as mean ± standard deviation. Statistical analysis was performed by analysis of variance (ANOVA) followed by posthoc Tukey’s multiple comparison test. Data was considered to be significant when P-value, p < 0.05.
(Comparative Examples 1-2 and Example 1)
To assess the influence of the excellent effect of the combination of cyclic dipeptides on the inflammatory marker, TNF-α, produced by the SIM-A9 microglial cells, following four different conditions were compared: cells before treatment (vehicle control), LPS-treated cells (Comparative Example 1), LPS + single cyclic dipeptide-treated cells (Comparative Example 2) and LPS + combination of four cyclic dipeptides (4DKPs)-treated cells (Example 1). LPS + single cyclic dipeptide-treated cells were pre-treated with LPS and any one of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro) and Cyclo(Val-Pro). In the pre-treatment, Cyclo(Phe-Phe) concentration was 22 μg/mL, Cyclo(Gly-Pro) concentration was 71 μg/mL, Cyclo(His-Pro) concentration was 28 μg/mL, Cyclo(Val-Pro) concentration was 34 μg/mL. In the LPS + 4DKPs-treated cells, the concentration of each cyclic dipeptide in 4DKPs was 22 μg/mL for Cyclo(Phe-Phe), 71 μg/mL for Cyclo(Gly-Pro), 28 μg/mL for Cyclo(His-Pro) and 34 μg/mL for Cyclo(Val-Pro).
As shown in Table 1, combination of four cyclic dipeptides provided an excellent effect in reducing inflammation compared to treatment with single cyclic dipeptide. Data is represented as means ± SD (n=3). * denotes significant difference with p<0.05, ** denotes p<0.01, *** denotes p<0.001 against vehicle control (untreated) unless indicated. # denotes significant difference with p<0.05, ## denotes p<0.01, ### denotes p<0.001 against LPS-treated cells unless indicated. $ denotes significant difference with p<0.05, $$ denotes p<0.01, $$$ denotes p<0.001 against LPS + single cyclic dipeptide-treated cells unless indicated. The name of cyclic dipeptide in parentheses after the $, $$ or $$$ mark indicates the cyclic dipeptide to which 4DKP has a significant difference.
To assess the influence of the excellent effect of the combination of cyclic dipeptides on the inflammatory marker, TNF-α, produced by the SIM-A9 microglial cells, following four different conditions were compared: cells before treatment (vehicle control), LPS-treated cells (Comparative Example 1), LPS + single cyclic dipeptide-treated cells (Comparative Example 2) and LPS + combination of four cyclic dipeptides (4DKPs)-treated cells (Example 1). LPS + single cyclic dipeptide-treated cells were pre-treated with LPS and any one of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro) and Cyclo(Val-Pro). In the pre-treatment, Cyclo(Phe-Phe) concentration was 22 μg/mL, Cyclo(Gly-Pro) concentration was 71 μg/mL, Cyclo(His-Pro) concentration was 28 μg/mL, Cyclo(Val-Pro) concentration was 34 μg/mL. In the LPS + 4DKPs-treated cells, the concentration of each cyclic dipeptide in 4DKPs was 22 μg/mL for Cyclo(Phe-Phe), 71 μg/mL for Cyclo(Gly-Pro), 28 μg/mL for Cyclo(His-Pro) and 34 μg/mL for Cyclo(Val-Pro).
As shown in Table 1, combination of four cyclic dipeptides provided an excellent effect in reducing inflammation compared to treatment with single cyclic dipeptide. Data is represented as means ± SD (n=3). * denotes significant difference with p<0.05, ** denotes p<0.01, *** denotes p<0.001 against vehicle control (untreated) unless indicated. # denotes significant difference with p<0.05, ## denotes p<0.01, ### denotes p<0.001 against LPS-treated cells unless indicated. $ denotes significant difference with p<0.05, $$ denotes p<0.01, $$$ denotes p<0.001 against LPS + single cyclic dipeptide-treated cells unless indicated. The name of cyclic dipeptide in parentheses after the $, $$ or $$$ mark indicates the cyclic dipeptide to which 4DKP has a significant difference.
(Comparative Examples 3-4 and Example 2)
The excellent effect of the combination of cyclic dipeptides on the inflammatory marker was examined in the same manner as in Example 1 and Comparative Examples 1-2, except that cells having the passage number of 16 (P16) were used and cultured in a medium not containing DMSO. In Table 2, “SFM control” means “serum-free medium control”.
As shown in Table 2, * denotes significant difference with p<0.05, ** denotes p<0.01, *** denotes p<0.001 against SFM control (untreated) unless indicated.
The excellent effect of the combination of cyclic dipeptides on the inflammatory marker was examined in the same manner as in Example 1 and Comparative Examples 1-2, except that cells having the passage number of 16 (P16) were used and cultured in a medium not containing DMSO. In Table 2, “SFM control” means “serum-free medium control”.
As shown in Table 2, * denotes significant difference with p<0.05, ** denotes p<0.01, *** denotes p<0.001 against SFM control (untreated) unless indicated.
<Evaluation method of inhibition of the production of NO>
In Examples and Comparative Examples, the effect of inhibiting the production of nitric oxide (NO) was evaluated by the following method.
Same reagents and statistical analyses were used as the evaluation method of anti-inflammatory activity.
In Examples and Comparative Examples, the effect of inhibiting the production of nitric oxide (NO) was evaluated by the following method.
Same reagents and statistical analyses were used as the evaluation method of anti-inflammatory activity.
(Cell culture and Treatments)
For Nitrite assay, cells were plated in a PLL-coated 96-well plate, at 20000 cells/well. Each of four cyclic dipeptides or a combination of four cyclic dipeptides was added to the cells separately and the cells were pre-incubated for 24 hours. After the pre-incubation period, LPS was added at 2.5μg/mL for a further 24 hours. Cells were centrifuged at 1,000rpm for 5 min. Supernatant was collected and assayed 48 hours post-plating.
For Nitrite assay, cells were plated in a PLL-coated 96-well plate, at 20000 cells/well. Each of four cyclic dipeptides or a combination of four cyclic dipeptides was added to the cells separately and the cells were pre-incubated for 24 hours. After the pre-incubation period, LPS was added at 2.5μg/mL for a further 24 hours. Cells were centrifuged at 1,000rpm for 5 min. Supernatant was collected and assayed 48 hours post-plating.
(Nitrite Analysis)
To determine the amount of nitric oxide (NO) produced, the culture medium collected was incubated with Griess Reagent (Promega) according to manufacturer’s instructions. Nitrite ion (NO2 -), a stable derivative of NO, was measured and quantified with a plate reader at 540nm (ref 690nm).
To determine the amount of nitric oxide (NO) produced, the culture medium collected was incubated with Griess Reagent (Promega) according to manufacturer’s instructions. Nitrite ion (NO2 -), a stable derivative of NO, was measured and quantified with a plate reader at 540nm (ref 690nm).
(Comparative Examples 5-6 and Example 3)
To assess the influence of the excellent effect of the combination of cyclic dipeptides on the production of NO produced by the SIM-A9 microglial cells, following four different conditions were compared: cells before treatment (vehicle control), LPS-treated cells (Comparative Example 5), LPS + single cyclic dipeptide-treated cells (Comparative Example 6) and LPS + 4DKPs-treated cells (Example 3). LPS + single cyclic dipeptide-treated cells were pre-treated with LPS and any one of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro) and Cyclo(Val-Pro). In the pre-treatment, Cyclo(Phe-Phe) concentration was 22 μg/mL, Cyclo(Gly-Pro) concentration was 71 μg/mL, Cyclo(His-Pro) concentration was 28 μg/mL, Cyclo(Val-Pro) concentration was 34 μg/mL. In the LPS + 4DKPs-treated cells, the concentration of each cyclic dipeptide in 4DKPs was 22 μg/mL for Cyclo(Phe-Phe), 71 μg/mL for Cyclo(Gly-Pro), 28 μg/mL for Cyclo(His-Pro) and 34 μg/mL for Cyclo(Val-Pro).
As shown in Table 3, combination of four cyclic dipeptides provided an excellent effect in reducing production of NO compared to treatment with single cyclic dipeptide. Data is represented as means ± SD (n=3). * denotes significant difference with p<0.05, ** denotes p<0.01, *** denotes p<0.001 against vehicle control (untreated) unless indicated. # denotes significant difference with p<0.05, ## denotes p<0.01, ### denotes p<0.001 against LPS-treated cells unless indicated. $ denotes significant difference with p<0.05, $$ denotes p<0.01, $$$ denotes p<0.001 against LPS + single cyclic dipeptide-treated cells unless indicated. The name of cyclic dipeptide in parentheses after the $, $$ or $$$ mark indicates the cyclic dipeptide to which 4DKP has a significant difference.
To assess the influence of the excellent effect of the combination of cyclic dipeptides on the production of NO produced by the SIM-A9 microglial cells, following four different conditions were compared: cells before treatment (vehicle control), LPS-treated cells (Comparative Example 5), LPS + single cyclic dipeptide-treated cells (Comparative Example 6) and LPS + 4DKPs-treated cells (Example 3). LPS + single cyclic dipeptide-treated cells were pre-treated with LPS and any one of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro) and Cyclo(Val-Pro). In the pre-treatment, Cyclo(Phe-Phe) concentration was 22 μg/mL, Cyclo(Gly-Pro) concentration was 71 μg/mL, Cyclo(His-Pro) concentration was 28 μg/mL, Cyclo(Val-Pro) concentration was 34 μg/mL. In the LPS + 4DKPs-treated cells, the concentration of each cyclic dipeptide in 4DKPs was 22 μg/mL for Cyclo(Phe-Phe), 71 μg/mL for Cyclo(Gly-Pro), 28 μg/mL for Cyclo(His-Pro) and 34 μg/mL for Cyclo(Val-Pro).
As shown in Table 3, combination of four cyclic dipeptides provided an excellent effect in reducing production of NO compared to treatment with single cyclic dipeptide. Data is represented as means ± SD (n=3). * denotes significant difference with p<0.05, ** denotes p<0.01, *** denotes p<0.001 against vehicle control (untreated) unless indicated. # denotes significant difference with p<0.05, ## denotes p<0.01, ### denotes p<0.001 against LPS-treated cells unless indicated. $ denotes significant difference with p<0.05, $$ denotes p<0.01, $$$ denotes p<0.001 against LPS + single cyclic dipeptide-treated cells unless indicated. The name of cyclic dipeptide in parentheses after the $, $$ or $$$ mark indicates the cyclic dipeptide to which 4DKP has a significant difference.
Claims (13)
- Use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) in the production of an agent for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- The use according to claim 1,
wherein the cognitive dysfunction is aging-related cognitive dysfunction. - The use according to claim 1 or 2,
wherein the cognitive function includes at least one selected from the group consisting of memory function, executive function, attention, and concentration. - The use according to claim 3,
wherein the memory function includes at least one selected from the group consisting of verbal memory function, nonverbal memory function, visuospatial memory function, gist memory function, and working memory function. - The use according to any one of claims 1 to 4,
wherein the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of inflammation in the brain. - The use according to claim 5,
wherein the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit the inflammation in the brain by inhibition of the production of nitric oxide. - The use according to any one of claims 1 to 5,
wherein the Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) inhibit a decline in cognitive function or ameliorate cognitive dysfunction by inhibition of the production of tumor necrosis factor-α (TNF-α). - The use according to any one of claims 1 to 7,
wherein the agent is for oral administration. - The use according to any one of claims 1 to 8,
wherein the agent is a food or beverage, or pharmaceutical product. - The use according to any one of claims 1 to 9,
wherein the agent is labeled with one or more function claims selected from the group consisting of "enhancing cognitive function", "inhibiting a decline in cognitive function", "maintaining good cognitive function", "improving memory", "inhibiting a decline in memory", "maintaining good memory", "improving accuracy of memory", "preventing memory disorders", "ameliorating memory disorders", "maintaining memory that is one domain of cognitive function", "function suitable for those who are concerned about a decline in memory", "improving accuracy of memory and/or correctness of judgement that are part of cognitive function", "improving memory retention or consolidation", "sustaining cognitive enhancement", "improving executive function", "promoting attention and concentration", "improving learning ability", "delaying aging-related cognitive decline", "enhancing short-term and long-term memory" and "promoting verbal and visuospatial memory". - Use of Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction.
- A composition for inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, comprising:
Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro) as active ingredients. - A method of inhibiting a decline in cognitive function or ameliorating cognitive dysfunction, comprising:
administering or feeding Cyclo(Phe-Phe), Cyclo(Gly-Pro), Cyclo(His-Pro), and Cyclo(Val-Pro).
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2023537334A JP2024500803A (en) | 2020-12-18 | 2021-12-03 | Use of cyclic dipeptide in the production of an agent for suppressing cognitive decline or improving cognitive dysfunction |
| AU2021401193A AU2021401193A1 (en) | 2020-12-18 | 2021-12-03 | Use of cyclic dipeptides in production of agent for inhibiting decline in cognitive function or ameliorating cognitive dysfunction |
| CN202180085186.3A CN116685343A (en) | 2020-12-18 | 2021-12-03 | Use of cyclic dipeptides for the manufacture of agents that inhibit cognitive decline or improve cognitive dysfunction |
| KR1020237024369A KR20230121869A (en) | 2020-12-18 | 2021-12-03 | Use of a cyclic dipeptide in the manufacture of an agent for inhibiting decline in cognitive function or ameliorating cognitive dysfunction |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SG10202012809X | 2020-12-18 | ||
| SG10202012809X | 2020-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022131026A1 true WO2022131026A1 (en) | 2022-06-23 |
Family
ID=82057645
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2021/044490 WO2022131026A1 (en) | 2020-12-18 | 2021-12-03 | Use of cyclic dipeptides in production of agent for inhibiting decline in cognitive function or ameliorating cognitive dysfunction |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP2024500803A (en) |
| KR (1) | KR20230121869A (en) |
| CN (1) | CN116685343A (en) |
| AU (1) | AU2021401193A1 (en) |
| TW (1) | TW202241486A (en) |
| WO (1) | WO2022131026A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024095906A1 (en) * | 2022-11-01 | 2024-05-10 | サントリーホールディングス株式会社 | Composition for preventing or inhibiting inflammation of neural cells |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150297584A1 (en) * | 2012-11-21 | 2015-10-22 | Suntory Holdings Limited | Learning and memory improver |
| WO2017010538A1 (en) * | 2015-07-16 | 2017-01-19 | サントリーホールディングス株式会社 | Composition that contains plant- or animal-derived peptide and inhibits serum carnosinase |
| WO2017119476A1 (en) * | 2016-01-08 | 2017-07-13 | サントリーホールディングス株式会社 | Composition for preventing neurological diseases |
| JP6598412B1 (en) * | 2019-06-04 | 2019-10-30 | ゼライス株式会社 | Food for improving cognitive function |
-
2021
- 2021-12-03 CN CN202180085186.3A patent/CN116685343A/en active Pending
- 2021-12-03 AU AU2021401193A patent/AU2021401193A1/en active Pending
- 2021-12-03 KR KR1020237024369A patent/KR20230121869A/en unknown
- 2021-12-03 WO PCT/JP2021/044490 patent/WO2022131026A1/en active Application Filing
- 2021-12-03 JP JP2023537334A patent/JP2024500803A/en active Pending
- 2021-12-16 TW TW110147227A patent/TW202241486A/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150297584A1 (en) * | 2012-11-21 | 2015-10-22 | Suntory Holdings Limited | Learning and memory improver |
| WO2017010538A1 (en) * | 2015-07-16 | 2017-01-19 | サントリーホールディングス株式会社 | Composition that contains plant- or animal-derived peptide and inhibits serum carnosinase |
| WO2017119476A1 (en) * | 2016-01-08 | 2017-07-13 | サントリーホールディングス株式会社 | Composition for preventing neurological diseases |
| JP6598412B1 (en) * | 2019-06-04 | 2019-10-30 | ゼライス株式会社 | Food for improving cognitive function |
Non-Patent Citations (4)
| Title |
|---|
| BELLEZZA ILARIA; GROTTELLI SILVIA; MIERLA ANNA LISA; CACCIATORE IVANA; FORNASARI ERIKA; ROSCINI LUCA; CARDINALI GIANLUIGI; MINELLI: "Neuroinflammation and endoplasmic reticulum stress are coregulated by cyclo(His-Pro) to prevent LPS neurotoxicity", INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 51, 31 March 2014 (2014-03-31), AMSTERDAM, NL, pages 159 - 169, XP029026619, ISSN: 1357-2725, DOI: 10.1016/j.biocel.2014.03.023 * |
| KANG HYEJIN; KU SAE-KWANG; CHOI HYUKJAE; BAE JONG-SUP: "Three diketopiperazines frommarine-derived bacteriainhibit LPS-induced endothelial inflammatory responses", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 26, no. 8, 10 March 2016 (2016-03-10), AMSTERDAM, NL , pages 1873 - 1876, XP029470666, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2016.03.030 * |
| LEE DAHAE, LEE SEOUNG RAK, KANG KI SUNG, KIM KI HYUN: "Bioactive Phytochemicals from Mulberry: Potential Anti-Inflammatory Effects in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 22, no. 15, pages 8120, XP055943651, DOI: 10.3390/ijms22158120 * |
| TURKEZ HASAN, CACCIATORE IVANA, ARSLAN MEHMET ENES, FORNASARI ERIKA, MARINELLI LISA, DI STEFANO ANTONIO, MARDINOGLU ADIL: "Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates", BIOMOLECULES, vol. 10, no. 5, pages 737, XP055943647, DOI: 10.3390/biom10050737 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024095906A1 (en) * | 2022-11-01 | 2024-05-10 | サントリーホールディングス株式会社 | Composition for preventing or inhibiting inflammation of neural cells |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2024500803A (en) | 2024-01-10 |
| CN116685343A (en) | 2023-09-01 |
| TW202241486A (en) | 2022-11-01 |
| KR20230121869A (en) | 2023-08-21 |
| AU2021401193A1 (en) | 2023-06-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5500522B2 (en) | Food or pharmaceutical composition containing tricyclic diterpenes and derivatives thereof for the treatment of depression | |
| WO2010106798A1 (en) | Agent for promoting energy consumption | |
| WO2022131026A1 (en) | Use of cyclic dipeptides in production of agent for inhibiting decline in cognitive function or ameliorating cognitive dysfunction | |
| US20230201255A1 (en) | Composition comprising cinnamaldehyde and zinc to improve swallowing | |
| EP3133941B1 (en) | Composition for using cinnamaldehyde and zinc for weight management | |
| TW202342088A (en) | Composition for minimizing production and/or accumulation of amyloid [beta] | |
| WO2021193820A1 (en) | Composition for promoting hair thickening, composition for sustaining growth phase in hair cycle and composition for promoting vegf production, composition for promoting transition from resting phase to growth phase in hair cycle and composition for promoting fgf7 production, and composition for promoting hair cycle normalization | |
| WO2024095905A1 (en) | COMPOSITION FOR SUPPRESSING AMYLOID β ACCUMULATION | |
| WO2023120408A1 (en) | Composition for suppressing or ameliorating cognitive function decline | |
| JP7026422B1 (en) | Beverage | |
| WO2024095906A1 (en) | Composition for preventing or inhibiting inflammation of neural cells | |
| CN113491334B (en) | nutritional composition | |
| WO2021131104A1 (en) | Composition containing peptide, production method thereof, and use of peptide | |
| WO2024004931A1 (en) | Immunomodulation composition | |
| JP7244002B2 (en) | Prophylactic and therapeutic drugs for alcoholism and food for prevention and treatment of alcoholism | |
| EP4066897A1 (en) | Composition for preventing decrease in muscle mass, preventing weakness of muscular power, increasing muscle mass or strengthening muscular power | |
| JP7301810B2 (en) | Peptides that improve cognitive function | |
| WO2021131570A1 (en) | Composition for ameliorating or suppressing decline of cognitive functions | |
| JP2022057307A (en) | Ammonia metabolism accelerator | |
| TW202417462A (en) | Immunomodulatory composition | |
| JP2023508940A (en) | Beverage composition containing peptide and/or salt thereof, method for producing the same, use of type 2 collagen hydrolyzate, composition for suppressing bone resorption, and use of chicken extract | |
| JP2022007697A (en) | Composition for improving brain functions | |
| KR20200128478A (en) | A composition for immune enhancement of toxoplasmosis comprising Ursolic acid | |
| CN110150469A (en) | A kind of livestock and poultry premixed feed and its preparation and feeding method with antiviral efficacy | |
| JP2019182775A (en) | Compositions for promoting delayed melatonin secretion onset time, compositions for improving early wakening and compositions for improving advanced circadian rhythm phase |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21906389 Country of ref document: EP Kind code of ref document: A1 |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 202180085186.3 Country of ref document: CN |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2023537334 Country of ref document: JP |
|
| ENP | Entry into the national phase |
Ref document number: 2021401193 Country of ref document: AU Date of ref document: 20211203 Kind code of ref document: A |
|
| ENP | Entry into the national phase |
Ref document number: 20237024369 Country of ref document: KR Kind code of ref document: A |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21906389 Country of ref document: EP Kind code of ref document: A1 |