JP2020158506A - 神経興奮性および運動行動を調節するための組成物および方法 - Google Patents
神経興奮性および運動行動を調節するための組成物および方法 Download PDFInfo
- Publication number
- JP2020158506A JP2020158506A JP2020079949A JP2020079949A JP2020158506A JP 2020158506 A JP2020158506 A JP 2020158506A JP 2020079949 A JP2020079949 A JP 2020079949A JP 2020079949 A JP2020079949 A JP 2020079949A JP 2020158506 A JP2020158506 A JP 2020158506A
- Authority
- JP
- Japan
- Prior art keywords
- mir
- expression
- activity
- seizures
- mice
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 75
- 239000000203 mixture Substances 0.000 title claims abstract description 21
- 230000008587 neuronal excitability Effects 0.000 title 1
- 108091070946 miR-128 stem-loop Proteins 0.000 claims abstract description 263
- 230000014509 gene expression Effects 0.000 claims abstract description 101
- 206010015037 epilepsy Diseases 0.000 claims abstract description 66
- 230000000694 effects Effects 0.000 claims abstract description 64
- 230000001965 increasing effect Effects 0.000 claims abstract description 52
- 210000004556 brain Anatomy 0.000 claims abstract description 48
- 238000011161 development Methods 0.000 claims abstract description 18
- 208000005809 status epilepticus Diseases 0.000 claims abstract description 13
- 206010010904 Convulsion Diseases 0.000 claims description 143
- 210000004027 cell Anatomy 0.000 claims description 55
- 239000003814 drug Substances 0.000 claims description 50
- 238000011282 treatment Methods 0.000 claims description 34
- 239000003795 chemical substances by application Substances 0.000 claims description 33
- 229940079593 drug Drugs 0.000 claims description 33
- 239000002773 nucleotide Substances 0.000 claims description 26
- 125000003729 nucleotide group Chemical group 0.000 claims description 26
- 210000001320 hippocampus Anatomy 0.000 claims description 25
- 102000039446 nucleic acids Human genes 0.000 claims description 23
- 108020004707 nucleic acids Proteins 0.000 claims description 23
- 150000007523 nucleic acids Chemical class 0.000 claims description 23
- 208000036572 Myoclonic epilepsy Diseases 0.000 claims description 17
- 201000007547 Dravet syndrome Diseases 0.000 claims description 16
- 206010073677 Severe myoclonic epilepsy of infancy Diseases 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 208000029028 brain injury Diseases 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 208000035475 disorder Diseases 0.000 claims description 13
- 238000001727 in vivo Methods 0.000 claims description 13
- 210000003169 central nervous system Anatomy 0.000 claims description 12
- 208000006011 Stroke Diseases 0.000 claims description 11
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 claims description 9
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 claims description 9
- 239000013603 viral vector Substances 0.000 claims description 9
- 208000015181 infectious disease Diseases 0.000 claims description 8
- 210000004962 mammalian cell Anatomy 0.000 claims description 8
- 206010021143 Hypoxia Diseases 0.000 claims description 7
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 7
- 239000001961 anticonvulsive agent Substances 0.000 claims description 7
- 230000006931 brain damage Effects 0.000 claims description 7
- 231100000874 brain damage Toxicity 0.000 claims description 7
- 230000007954 hypoxia Effects 0.000 claims description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 230000009529 traumatic brain injury Effects 0.000 claims description 7
- 208000023275 Autoimmune disease Diseases 0.000 claims description 6
- 208000030159 metabolic disease Diseases 0.000 claims description 6
- 230000002503 metabolic effect Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229960003965 antiepileptics Drugs 0.000 claims description 5
- 230000007170 pathology Effects 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 4
- 230000000926 neurological effect Effects 0.000 claims description 4
- 230000001575 pathological effect Effects 0.000 claims description 2
- 241000699670 Mus sp. Species 0.000 description 128
- 108700011259 MicroRNAs Proteins 0.000 description 48
- 108091084874 miR-128-2 stem-loop Proteins 0.000 description 43
- 230000037023 motor activity Effects 0.000 description 43
- 108090000623 proteins and genes Proteins 0.000 description 40
- 210000002569 neuron Anatomy 0.000 description 38
- 241000699666 Mus <mouse, genus> Species 0.000 description 34
- 230000007812 deficiency Effects 0.000 description 29
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 26
- 239000002679 microRNA Substances 0.000 description 26
- 210000001577 neostriatum Anatomy 0.000 description 23
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 20
- 230000002018 overexpression Effects 0.000 description 19
- 239000013598 vector Substances 0.000 description 19
- 239000007924 injection Substances 0.000 description 18
- 238000002347 injection Methods 0.000 description 18
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 17
- 108091059786 miR-128-1 stem-loop Proteins 0.000 description 17
- 229940124597 therapeutic agent Drugs 0.000 description 17
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 16
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 108020004999 messenger RNA Proteins 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 14
- 239000013612 plasmid Substances 0.000 description 14
- 206010001497 Agitation Diseases 0.000 description 13
- 108700028369 Alleles Proteins 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 230000006399 behavior Effects 0.000 description 13
- 230000018109 developmental process Effects 0.000 description 13
- 229960003638 dopamine Drugs 0.000 description 13
- 230000008685 targeting Effects 0.000 description 13
- 239000000523 sample Substances 0.000 description 12
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 230000002950 deficient Effects 0.000 description 11
- 108091034117 Oligonucleotide Proteins 0.000 description 10
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 10
- 230000034994 death Effects 0.000 description 10
- 210000001787 dendrite Anatomy 0.000 description 10
- 208000013403 hyperactivity Diseases 0.000 description 10
- 230000013011 mating Effects 0.000 description 10
- 102000042567 non-coding RNA Human genes 0.000 description 10
- 108091027963 non-coding RNA Proteins 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 230000002269 spontaneous effect Effects 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000001790 Welch's t-test Methods 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 230000008499 blood brain barrier function Effects 0.000 description 9
- 210000001218 blood-brain barrier Anatomy 0.000 description 9
- 230000001537 neural effect Effects 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 9
- GHWJEDJMOVUXEC-UHFFFAOYSA-N 9-chloro-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol Chemical compound C1NCCC=2C(Cl)=C(O)C(O)=CC=2C1C1=CC=CC=C1 GHWJEDJMOVUXEC-UHFFFAOYSA-N 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 238000011529 RT qPCR Methods 0.000 description 8
- 230000002159 abnormal effect Effects 0.000 description 8
- 108010083633 cyclic AMP-regulated phosphoprotein ARPP-21 Proteins 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- -1 phospho Chemical class 0.000 description 8
- 102000040430 polynucleotide Human genes 0.000 description 8
- 108091033319 polynucleotide Proteins 0.000 description 8
- 239000002157 polynucleotide Substances 0.000 description 8
- 238000001890 transfection Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000003213 activating effect Effects 0.000 description 7
- 230000005014 ectopic expression Effects 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 230000001665 lethal effect Effects 0.000 description 7
- 210000004379 membrane Anatomy 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 230000000392 somatic effect Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 206010061334 Partial seizures Diseases 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 description 6
- 210000005056 cell body Anatomy 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 230000002779 inactivation Effects 0.000 description 6
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 6
- 229950006874 kainic acid Drugs 0.000 description 6
- 231100000518 lethal Toxicity 0.000 description 6
- 230000033001 locomotion Effects 0.000 description 6
- 108091070501 miRNA Proteins 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 210000004129 prosencephalon Anatomy 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- MLACDGUOKDOLGC-UHFFFAOYSA-N 5-(2-aminoethyl)benzene-1,2,4-triol;hydron;bromide Chemical compound Br.NCCC1=CC(O)=C(O)C=C1O MLACDGUOKDOLGC-UHFFFAOYSA-N 0.000 description 5
- 208000001654 Drug Resistant Epilepsy Diseases 0.000 description 5
- 208000018737 Parkinson disease Diseases 0.000 description 5
- LHNKBXRFNPMIBR-UHFFFAOYSA-N Picrotoxin Natural products CC(C)(O)C1(O)C2OC(=O)C1C3(O)C4OC4C5C(=O)OC2C35C LHNKBXRFNPMIBR-UHFFFAOYSA-N 0.000 description 5
- 108020004459 Small interfering RNA Proteins 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000003542 behavioural effect Effects 0.000 description 5
- 229960003920 cocaine Drugs 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 238000003205 genotyping method Methods 0.000 description 5
- 210000004602 germ cell Anatomy 0.000 description 5
- 230000000971 hippocampal effect Effects 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 108091055434 miR-124a stem-loop Proteins 0.000 description 5
- 108091082871 miR-124a-2 stem-loop Proteins 0.000 description 5
- 108091050112 miR-124a-4 stem-loop Proteins 0.000 description 5
- 108091054623 miR-124a-5 stem-loop Proteins 0.000 description 5
- 108091024680 miR-124a-6 stem-loop Proteins 0.000 description 5
- 231100000878 neurological injury Toxicity 0.000 description 5
- VJKUPQSHOVKBCO-AHMKVGDJSA-N picrotoxin Chemical compound O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(=C)C)[C@@H]1C(=O)O2.O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(C)(O)C)[C@@H]1C(=O)O2 VJKUPQSHOVKBCO-AHMKVGDJSA-N 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 230000002028 premature Effects 0.000 description 5
- 230000000306 recurrent effect Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000011830 transgenic mouse model Methods 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 101150110160 DRD1 gene Proteins 0.000 description 4
- 108700024394 Exon Proteins 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 102100039125 cAMP-regulated phosphoprotein 21 Human genes 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 230000001054 cortical effect Effects 0.000 description 4
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 238000010304 firing Methods 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 208000028325 tonic-clonic seizure Diseases 0.000 description 4
- 230000001052 transient effect Effects 0.000 description 4
- 238000007492 two-way ANOVA Methods 0.000 description 4
- 108020005345 3' Untranslated Regions Proteins 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 108091029865 Exogenous DNA Proteins 0.000 description 3
- 208000002091 Febrile Seizures Diseases 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 208000034308 Grand mal convulsion Diseases 0.000 description 3
- 101000885144 Homo sapiens cAMP-regulated phosphoprotein 21 Proteins 0.000 description 3
- 102000043136 MAP kinase family Human genes 0.000 description 3
- 108091054455 MAP kinase family Proteins 0.000 description 3
- 229940124647 MEK inhibitor Drugs 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001045988 Neogene Species 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002105 Southern blotting Methods 0.000 description 3
- 208000003443 Unconsciousness Diseases 0.000 description 3
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 3
- 230000036982 action potential Effects 0.000 description 3
- 238000009227 behaviour therapy Methods 0.000 description 3
- 210000005098 blood-cerebrospinal fluid barrier Anatomy 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 230000011712 cell development Effects 0.000 description 3
- 230000024245 cell differentiation Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 101150064107 fosB gene Proteins 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 238000007914 intraventricular administration Methods 0.000 description 3
- 230000006742 locomotor activity Effects 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 101150091879 neo gene Proteins 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 239000004055 small Interfering RNA Substances 0.000 description 3
- 230000000946 synaptic effect Effects 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 230000002123 temporal effect Effects 0.000 description 3
- 210000001103 thalamus Anatomy 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 239000012109 Alexa Fluor 568 Substances 0.000 description 2
- 108091032955 Bacterial small RNA Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000033001 Complex partial seizures Diseases 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 108020003215 DNA Probes Proteins 0.000 description 2
- 239000003298 DNA probe Substances 0.000 description 2
- 108010053187 Diphtheria Toxin Proteins 0.000 description 2
- 102000004076 Dopamine D1 Receptors Human genes 0.000 description 2
- 108090000511 Dopamine D1 Receptors Proteins 0.000 description 2
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 2
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- 241000257465 Echinoidea Species 0.000 description 2
- 108090000331 Firefly luciferases Proteins 0.000 description 2
- 101150007682 Gabrg2 gene Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000004547 Hallucinations Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 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 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- 108020005198 Long Noncoding RNA Proteins 0.000 description 2
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 2
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 208000037158 Partial Epilepsies Diseases 0.000 description 2
- 108091093037 Peptide nucleic acid Proteins 0.000 description 2
- 108091007412 Piwi-interacting RNA Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 102000009572 RNA Polymerase II Human genes 0.000 description 2
- 108010009460 RNA Polymerase II Proteins 0.000 description 2
- 101150022529 Scn1a gene Proteins 0.000 description 2
- 206010040703 Simple partial seizures Diseases 0.000 description 2
- 108020004688 Small Nuclear RNA Proteins 0.000 description 2
- 102000039471 Small Nuclear RNA Human genes 0.000 description 2
- 206010043994 Tonic convulsion Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 208000028311 absence seizure Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 101150084233 ago2 gene Proteins 0.000 description 2
- 238000011292 agonist therapy Methods 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 210000004720 cerebrum Anatomy 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000001037 epileptic effect Effects 0.000 description 2
- 230000021824 exploration behavior Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000012520 frozen sample Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000003633 gene expression assay Methods 0.000 description 2
- 230000035874 hyperreactivity Effects 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 230000003447 ipsilateral effect Effects 0.000 description 2
- 230000009191 jumping Effects 0.000 description 2
- 230000000366 juvenile effect Effects 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000001325 log-rank test Methods 0.000 description 2
- 238000003468 luciferase reporter gene assay Methods 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 229960004927 neomycin Drugs 0.000 description 2
- 230000007372 neural signaling Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 210000002729 polyribosome Anatomy 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000014493 regulation of gene expression Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 230000009183 running Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229940084026 sodium valproate Drugs 0.000 description 2
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 230000000542 thalamic effect Effects 0.000 description 2
- 230000005030 transcription termination Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 2
- 229960000604 valproic acid Drugs 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 2
- 229960001600 xylazine Drugs 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- OMDQUFIYNPYJFM-XKDAHURESA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[[(2r,3s,4r,5s,6r)-4,5,6-trihydroxy-3-[(2s,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]methoxy]oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@H](O)[C@H](O)O1 OMDQUFIYNPYJFM-XKDAHURESA-N 0.000 description 1
- GXIDBZKXGUNITQ-VIFPVBQESA-N (2s)-2-amino-5-(4-methoxy-7-nitro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid Chemical compound COC1=CC=C([N+]([O-])=O)C2=C1CCN2C(=O)CC[C@H](N)C(O)=O GXIDBZKXGUNITQ-VIFPVBQESA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- 102100021546 60S ribosomal protein L10 Human genes 0.000 description 1
- 240000005020 Acaciella glauca Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108091093088 Amplicon Proteins 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 101150068685 BTG2 gene Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 229930182476 C-glycoside Natural products 0.000 description 1
- 150000000700 C-glycosides Chemical class 0.000 description 1
- 101150069920 Camk2a gene Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010070666 Cortical dysplasia Diseases 0.000 description 1
- 108010051219 Cre recombinase Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 101150117962 DUSP1 gene Proteins 0.000 description 1
- 101100447432 Danio rerio gapdh-2 gene Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 description 1
- 238000003718 Dual-Luciferase Reporter Assay System Methods 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000701832 Enterobacteria phage T3 Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000000729 Fisher's exact test Methods 0.000 description 1
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101150066632 Gadd45g gene Proteins 0.000 description 1
- 229920000926 Galactomannan Polymers 0.000 description 1
- 101150112014 Gapdh gene Proteins 0.000 description 1
- 206010018341 Gliosis Diseases 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 108020005004 Guide RNA Proteins 0.000 description 1
- 206010019070 Hallucination, auditory Diseases 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 238000009015 Human TaqMan MicroRNA Assay kit Methods 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- 208000000269 Hyperkinesis Diseases 0.000 description 1
- 206010071081 Idiopathic generalised epilepsy Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000015592 Involuntary movements Diseases 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 101150026829 JUNB gene Proteins 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000254158 Lampyridae Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 239000012820 MEK1 Inhibitor Substances 0.000 description 1
- 208000000676 Malformations of Cortical Development Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 108091068766 Mus musculus miR-128-1 stem-loop Proteins 0.000 description 1
- 108091065180 Mus musculus miR-128-2 stem-loop Proteins 0.000 description 1
- 208000002033 Myoclonus Diseases 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 101150088803 NR4A1 gene Proteins 0.000 description 1
- 108091061960 Naked DNA Proteins 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 102000004108 Neurotransmitter Receptors Human genes 0.000 description 1
- 108090000590 Neurotransmitter Receptors Proteins 0.000 description 1
- 241000380800 Nordus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- YYHGQOLZRYICRS-UHFFFAOYSA-N Polycarpin Natural products C1=2C=C(OC)C(OC)=CC=2CCN(C=O)C1=CC1=CC=C(OC)C(OC)=C1O YYHGQOLZRYICRS-UHFFFAOYSA-N 0.000 description 1
- YYHGQOLZRYICRS-SXGWCWSVSA-N Polycarpine Polymers C1=2C=C(OC)C(OC)=CC=2CCN(C=O)\C1=C/C1=CC=C(OC)C(OC)=C1O YYHGQOLZRYICRS-SXGWCWSVSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 201000010273 Porphyria Cutanea Tarda Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102000017143 RNA Polymerase I Human genes 0.000 description 1
- 108010013845 RNA Polymerase I Proteins 0.000 description 1
- 102000014450 RNA Polymerase III Human genes 0.000 description 1
- 108010078067 RNA Polymerase III Proteins 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 239000013614 RNA sample Substances 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- 108010052090 Renilla Luciferases Proteins 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 108090000986 Ribosomal protein L10 Proteins 0.000 description 1
- 235000011449 Rosa Nutrition 0.000 description 1
- 101100174184 Serratia marcescens fosA gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000006180 TBST buffer Substances 0.000 description 1
- 241001365914 Taira Species 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- 108091061763 Triple-stranded DNA Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000000573 anti-seizure effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- NGPGDYLVALNKEG-UHFFFAOYSA-N azanium;azane;2,3,4-trihydroxy-4-oxobutanoate Chemical compound [NH4+].[NH4+].[O-]C(=O)C(O)C(O)C([O-])=O NGPGDYLVALNKEG-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 230000004641 brain development Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 150000001649 bromium compounds Chemical class 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
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000008004 cell lysis buffer Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 208000023397 cerebral cortical dysplasia Diseases 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 231100000749 chronicity Toxicity 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 230000002566 clonic effect Effects 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 208000030418 congenital vascular malformation Diseases 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000003179 convulsant agent Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000009509 cortical damage Effects 0.000 description 1
- 230000009537 cortical lesion Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 230000028436 dopamine uptake Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 201000009028 early myoclonic encephalopathy Diseases 0.000 description 1
- 230000001490 effect on brain Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000010201 enrichment analysis Methods 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 108700020302 erbB-2 Genes Proteins 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 206010016284 febrile convulsion Diseases 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 101150078861 fos gene Proteins 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000003371 gabaergic effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000003208 gene overexpression Methods 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000007387 gliosis Effects 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000003370 grooming effect Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 210000003917 human chromosome Anatomy 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000001660 hyperkinetic effect Effects 0.000 description 1
- 230000035873 hypermotility Effects 0.000 description 1
- 201000001993 idiopathic generalized epilepsy Diseases 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 239000012133 immunoprecipitate Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 108091024426 miR-1281 stem-loop Proteins 0.000 description 1
- 108091040501 miR-129 stem-loop Proteins 0.000 description 1
- 108091045757 miR-129-3 stem-loop Proteins 0.000 description 1
- 108091090758 miR-129-4 stem-loop Proteins 0.000 description 1
- 108091065139 miR-129-5 stem-loop Proteins 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000009038 pharmacological inhibition Effects 0.000 description 1
- 238000011422 pharmacological therapy Methods 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 108091005981 phosphorylated proteins Proteins 0.000 description 1
- 125000005642 phosphothioate group Chemical group 0.000 description 1
- 230000008832 photodamage Effects 0.000 description 1
- NUSQOFAKCBLANB-UHFFFAOYSA-N phthalocyanine tetrasulfonic acid Chemical compound C12=CC(S(=O)(=O)O)=CC=C2C(N=C2NC(C3=CC=C(C=C32)S(O)(=O)=O)=N2)=NC1=NC([C]1C=CC(=CC1=1)S(O)(=O)=O)=NC=1N=C1[C]3C=CC(S(O)(=O)=O)=CC3=C2N1 NUSQOFAKCBLANB-UHFFFAOYSA-N 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- GBYNZTPAERUJGY-UHFFFAOYSA-N polycarpine dihydrochloride Natural products C1=CC(OC)=CC=C1C1=C(SSC=2N(C(N)=NC=2C=2C=CC(OC)=CC=2)C)N(C)C(N)=N1 GBYNZTPAERUJGY-UHFFFAOYSA-N 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000007542 postnatal development Effects 0.000 description 1
- 230000001144 postural effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000216 proconvulsive effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 210000001176 projection neuron Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000010349 pulsation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 235000003499 redwood Nutrition 0.000 description 1
- 230000016515 regulation of signal transduction Effects 0.000 description 1
- 230000037425 regulation of transcription Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- MOCOXAJEZKHXSF-IHMBCTQLSA-M sodium;(2s,4as,6ar,6as,6br,8ar,10s,12as,14br)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-3,4,5,6,6a,7,8,8a,10,11,12,14b-dodecahydro-1h-picene-2-carboxylate Chemical compound [Na+].C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C([O-])=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MOCOXAJEZKHXSF-IHMBCTQLSA-M 0.000 description 1
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000003478 temporal lobe Anatomy 0.000 description 1
- 201000008914 temporal lobe epilepsy Diseases 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 230000017756 tolerance induction in nasopharyngeal-associated lymphoid tissue Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 230000009184 walking Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0276—Knock-out vertebrates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
- G01N33/5058—Neurological cells
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
- A01K2217/052—Animals comprising random inserted nucleic acids (transgenic) inducing gain of function
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/20—Animal model comprising regulated expression system
- A01K2217/203—Animal model comprising inducible/conditional expression system, e.g. hormones, tet
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
- A01K2267/0356—Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
- C12N2310/141—MicroRNAs, miRNAs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/321—2'-O-R Modification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/341—Gapmers, i.e. of the type ===---===
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
- C12N2310/3515—Lipophilic moiety, e.g. cholesterol
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/352—Nature of the modification linked to the nucleic acid via a carbon atom
- C12N2310/3521—Methyl
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Environmental Sciences (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Neurology (AREA)
- Public Health (AREA)
- Wood Science & Technology (AREA)
- Neurosurgery (AREA)
- Medicinal Chemistry (AREA)
- Biodiversity & Conservation Biology (AREA)
- Animal Husbandry (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Pathology (AREA)
- Cell Biology (AREA)
- Toxicology (AREA)
- Psychology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Plant Pathology (AREA)
- Food Science & Technology (AREA)
Abstract
Description
(A)miR−128−2の欠損が、マウスにおいて活動亢進および早発性死亡を引き起こす。(左側パネル)60分オープンフィールドアッセイで全水平距離を測定することによって、運動活動を測定した(n=23および12)。(右側パネル)miR−128−2−/−マウスおよび同腹子対照の寿命を示す(n=20および46)。(B、C)miR−128欠損は、抗痙攣薬治療によって予防することができる致死的発作を引き起こす。
(B)22日の観察期間中のmiR−128−2−/−(黒色)またはCamk2a−cre;miR−128−2fl/flマウス(赤色)における自発強直間代発作エピソードの代表的表示。
(C)対照miR−128−2−/−(点線、Aに示される通り)またはバルプロ酸ナトリウム処理(赤色、n=11)miR−128−2−/−マウスの寿命を示す。
(D)生後ニューロンのmiR−128の欠損が、活動亢進および致死的てんかんを引き起こす。Camk2a−cre;miR−128−2fl/flマウス(n=21および25)および同腹子(n=8および47)の運動活動および生存率を示す。
(E)miR−128の異所性発現が、Camk2a−cre;miR−128−2fl/flマウスの自発運動亢進を正常化し、死亡を防ぐことを示す。Camk2a−cre;miR−128−2fl/fl;Rosa−miR−128(n=4、青色)および野生型マウス(n=10、灰色)の運動活動を示す。異所性miR−128発現の存在下(n=4、青色)または非存在下(n=9、黒色)でのCamk2a−cre;miR−128−2fl/flマウスの寿命を示す。
(F)D1−ニューロンのmiR−128欠損が、活動亢進および致死的てんかんを引き起こす。D1−ニューロン特異的miR−128欠損を有するマウスまたは対照マウスの運動活動(n=26および42)および寿命(n=16および28)を示す。エラーバーは平均値の標準誤差、ウェルチのt検定、非有意(ns)、*p≦0.05、**p≦0.01、***p≦0.001を示す。カプラン・マイヤーグラフは、突然変異体および同腹子対照マウスの生存曲線、***p≦0.001、対数順位検定を示す。
(A、B)miR−128がD1−ニューロン樹状突起興奮性および棘の数を調節する。
(A)シグナル活動電位を細胞体で産生させ、遠位カルシウムシグナルを細胞1個当たりの最大近位カルシウムシグナルで割ることによって、活動電位侵入を計算した(n=4個の細胞、11〜21個の軸/群)。マン・ホイットニーのノンパラメトリック検定、***p≦0.001。
(B)対照および突然変異体D1−ニューロンの遠位樹状突起の代表的な最大強度投影像を示す。箱ひげ図は、集団棘密度(1群当たりn=10〜11個の細胞)を示す。マン・ホイットニーのノンパラメトリック検定、エラーバーは、第90パーセンタイル間隔、*p≦0.05を示す。(C〜E)miR−128は、D1−ニューロンにおける運動反応、ERK2リン酸化、およびドーパミンD1受容体(Drd1)活性化を受けた即時型遺伝子(IEG)誘導を調節する。
(C)Drd1a−cre;miR−128−2fl/flおよび対照マウス(n=25および30)の運動活動をオープンフィールドチャンバーで評価した。生理食塩水および3mg/kg Drg1アゴニストSKF81297をそれぞれ10分および20分に腹腔内注射した。
(D)生理食塩水またはD1アゴニストSKF81297注射を受けたDrg1a−cre;miR−128−2fl/flおよび対照マウス(それぞれn=5)に由来する線条体溶解物のウエスタンブロット法によって、ERK2リン酸化を定量化した。棒グラフは、ホスホERK2と全ERK2の発現の比を示す。
(E)生理食塩水またはSKF81297で処理したDrd1a−TRAP;Drd1a−cre;miR−128−2fl/flおよび対照マウスから精製したD1−ニューロン特異的ポリリボソーム結合mRNAのqRT−PCR(それぞれn=5)によって、IEGおよびD1−ニューロン発現Darpp32遺伝子発現レベルを測定した。エラーバーは平均値の標準誤差、ウェルチのt検定、*p≦0.05、**p≦0.01、***p≦0.001を示す。
(A)Drg1a−cre;miR−128−2fl/flおよび同腹子対照マウスに、ビヒクルまたは12mg/kgのMEK1阻害剤SL327のいずれかを腹腔内注射した(n=5/群)。薬物注射30分後のERK2リン酸化のウエスタンブロット解析(左)およびビヒクルまたはSL327注射後の運動活動(右)を示す。二元配置分散分析、引き続いてボンフェローニポストテスト。エラーバーは、平均値の標準誤差、*p≦0.05、**p≦0.01、***p≦0.001を示す。
(B)miR−128の過剰発現が、ドーパミン枯渇線条体においてD1−ニューロン反応性亢進を抑制する。片側性6−OHDA損傷Camk2a−cre;Rosa−miR−128または対照マウス(n=11/群)におけるベースラインでのおよびコカイン(10mg/kg)またはD1−アゴニストSKF81297(5mg/kg)に反応した反対側回転の数を示す。エラーバーは平均値の標準誤差、ウェルチのt検定、**p≦0.01を示す。
(D)miR−128がマウスの化学的誘発発作に対する感受性を低下させる。痙攣誘発薬(pro−convulsive drug)カイニン酸(30mg/kg、p値=0.005)またはピクロトキシン(3mg/kg、p値=0.04)の腹腔内注射60分後に強直間代発作を示すCamk2a−cre;Rosa−miR−128または同腹子対照マウス(n=12/群)の数を示す。p値はフィッシャーの正確確率検定によって計算した。
(A)miR−128がマウス脳内に豊富にある。8週齢成体マウスの脳、骨格筋、心臓、腎臓、肺および肝臓から精製したRNAにおけるqRT−PCR(n=3)によって、miR−128の発現レベルを測定した。miR−128の発現レベルをsnoRNA135発現に正規化し、肝臓におけるそれぞれのmiRNA発現レベルに対する倍率増加として示した。脳対他の器官の比較のための、一元配置分散分析、引き続いてテューキーのポストテスト、p<0.01。
(B)生後脳発達がmiR−128発現レベルの増加を伴う。miR−128およびニューロン富化miR−124aの発現レベルを、胚発生の12日目(E12)、新生マウス(P0)または8週齢成体マウス(1齢群当たりn=3)のマウス胚に由来する脳におけるqRT−PCRによって測定した。miRNAの発現レベルをsnoRNA135発現に正規化し、E12胚性脳におけるそれぞれのmiRNA発現レベルに対する倍率増加として示した。
(C)miR−128が異なる脳領域中で発現している。成体マウスの示される脳領域中のmiR−128の発現を、(A)のように定量化し、脳幹中の平均miR−128発現に対して示した(n=3/領域)。エラーバーは、平均値の標準誤差を示す。
(A、B)マウスの条件遺伝子不活性化のための(A)miR−128−1の生成(B)miR−128−2の生成。(左側パネル)miR−128遺伝子の遺伝子組換えおよび不活性化のための戦略を示す。miR−128保有遺伝子の両方のmiRNAヘアピンを含有する領域を、マウスES細胞のloxP部位と隣接させ、引き続いてmiR−128−1fl/flおよびmiR−128−2fl/flマウスの作成のための日常的手順を行った。マイクロRNAヘアピン、塗りつぶされた長方形;エクソン、空の長方形;loxP部位、黒色三角形。FRT配列(黒色円)が隣接したネオマイシン耐性遺伝子を、FLTリコンビナーゼを用いて標的化遺伝子座から除去した;DTA、ジフテリア毒素遺伝子;TK、チミジンキナーゼ遺伝子;LAH/SAH、相同性の長腕および短腕。(右側パネル)miR−128−1fl/flおよびmiR−128−2fl/flマウスをそれぞれCMV−creマウスと交配することによって、miR−128−1(miR−128−1−/−)またはmiR−128−2(miR−128−2−/−)欠損マウスを作成した。示されるDNAプローブ(黒色長方形)を用いるEcoRIもしくはSacIにより消化したマウス尾DNAのサザンブロット法、またはスキームに示されるプライマーを用いるPCR遺伝子型判定によって、組換えmiR−128−1およびmiR−128−2対立遺伝子を同定した。miR−128−1(それぞれn=7)またはmiR−128−2(n=5および3)遺伝子が欠損したマウスの線条体中のmiR−128の相対発現レベルを示す。
(C)miR−128−1遺伝子の不活性化は、マウスの運動活動にも生存にも影響を与えない。マウスの運動活動に対するmiR−128−1欠損の影響を、オープンフィールド分析を用いて測定した。オープンフィールドでの60分以内の(左側パネル)全移動水平距離(m)および(中央パネル)垂直立ち上がりエピソード数を示す(n=7および9)。(右側パネル)miR−128−1が欠損したマウス(n=6)およびそれぞれの野生型同腹子対照(n=22)の寿命を示す。
(D)miR−128−2遺伝子の不活性化がマウスの探索を増加させる。miR−128−2−/−および同腹子対照の垂直立ち上がりエピソードの数を示す(n=23および12)。エラーバーは平均値の標準誤差、*p≦0.05、**p≦0.01、ウェルチのt検定および対数順位検定を示す。
(A)生後Camk2a−ニューロンにおけるmiR−128欠損が探索を増加させる。Camk2a−creをmiR−128−2fl/flマウスと交配することによって、生後Camk2a−ニューロンにおけるmiR−128欠損を達成した。(左側パネル)棒グラフは、Camk2a−cre;miR−128−2fl/flマウスおよび対照同腹子(n=7および4)における相対miR−128発現レベルを示す。(右側パネル)Camk2a−cre;miR−128−2fl/flマウスおよび対照同腹子(n=21および8)によって行われた垂直立ち上がりエピソードの数を示す。
(B)D1−ニューロンにおけるmiR−128欠損が探索を増加させる。Drd1a−creをmiR−128−2fl/flマウスと交配することによって、D1−ニューロンにおけるmiR−128欠損を達成した。Drd1a−cre;miR−128−2fl/flマウスおよび対照同腹子(n=22および26)の相対線条体miR−128発現レベル(左側、それぞれn=3)および垂直立ち上がりエピソード(右側)を示す。
(C)D2−ニューロンにおけるmiR−128欠損がマウスの運動活動にも生存にも影響を与えない。A2A−creをmiR−128−2fl/flマウスと交配することによって、D2−ニューロンにおけるmiR−128欠損を達成した。A2A−cre;miR−128−2fl/flマウスおよびそれぞれの同腹子(n=7)の線条体miR−128発現レベル(左側、それぞれn=3)、水平運動活動および垂直立ち上がりエピソード(中央、n=9および7)ならびに生存期間(右側、n=8および7)を示す。エラーバーは平均値の標準誤差、*p≦0.05、**p≦0.01、ウェルチのt検定および対数順位検定を示す。
(A)miR−128の条件付き過剰発現を有するマウスを作成するための標的化戦略。前記のノックイン戦略を用いて、外因性miR−128−2遺伝子をES細胞の内因性Rosa26遺伝子座に挿入した。miR−128−2遺伝子(赤色長方形)を、floxed−STOP−ネオマイシンカセットによって強力なCAGGプロモーターから分離した。エクソン、灰色長方形。DTA、ジフテリア毒素遺伝子。示されるDNAプローブ(青色長方形)を用いるEcoPI消化DNA(右上)のサザンブロット解析、またはPCR遺伝子型判定(右下、スキームに示されるプライマー位置)によって、組換えROSA−Stopfl/fl−miR−128対立遺伝子(単純化のために今からRosa−miR−128と呼ぶ)を確認した。
(B)miR−128のニューロン特異的過剰発現を有するマウスにおける運動活動および探索の減少。(上部)Camk2a−creをRosa−miR−128マウスと交配することによって、miR−128の生後ニューロン特異的過剰発現を有するマウス(Camk2a−cre;Rosa−miR−128)を作成した。(左側)線条体におけるmiR−128発現レベルを上記のように(図4)qRT−PCRによって測定し(それぞれn=3)、野生型線条体における平均miR−128発現に対して示す。ウェルチのt検定。(中央および右側)Camk2a−cre;Rosa−miR−128マウス(n=21)および同腹子対照(野生型n=8、Camk2a−cre n=5、Rosa−miR−128 n=17)についての60分間にわたるオープンフィールドでの全水平距離および立ち上がり活動を示す。一元配置分散分析、引き続いてテューキーのポストテスト。
(C)Rosa26遺伝子座からのmiR−128の異所性発現が、Camk2a−cre;miR−128−2fl/flマウスにおけるmiR−128発現レベルを正常化する。(左側)Camk2a−cre;miR−128−2fl/flをRosa−miR−128マウスと交配することによって、miR−128−2の生後ニューロン特異的ノックアウトおよびRosa26遺伝子座からのmiR−128−2の異所性発現を有するマウス(Camk2a−cre;miR−128−2fl/fl;Rosa−miR−128)を作成した。(右側)Camk2a−cre;miR−128−2fl/fl;Rosa−miR−128マウス(n=4)の線条体におけるmiR−128発現をqRT−PCRによって測定し、データを同腹子対照(n=3)における平均発現に対して示す。ウェルチのt検定。エラーバーは、平均値の標準誤差、*p≦0.05、**p≦0.01を示す。
(A、左側)体性電流注入に対する対照(Drd−1a−TRAP;miR−128−2fl/fl、上部、黒色)およびmiR−128欠損(Drd1a−TRAP、Drd1a−cre;miR−128fl/fl、底部、赤色)D1−ニューロンの代表的なD1−ニューロン原型反応。D1−ニューロンを、eGFP−L10発現によって同定し、電圧トレースは−100、−50、+100、+190および+250pAに応じたものである。(A、右側)体性電流注入に対するD1−ニューロン特徴的平均発火頻度を示す頻度−電流(F−I)プロット。野生型(黒色、n=6)D1ニューロンと突然変異(赤色、n=7)D1−ニューロンとの間に差は観察されなかった。マン・ホイットニーのノンパラメトリック検定、p>0.05。
(B)miR−128がD1−ニューロン中の機能的棘の数を制御する。連続的な隣接棘頭に対するグルタミン酸の二光子アンケージングによって、対照とmiR−128欠損D1−ニューロン(n=5〜6個の細胞、1群当たり40〜48本の棘、左側)の体性EPSCを生成する同様の成功率が明らかになり、(図3B)中の棘密度の増加が機能的グルタミン酸受容体を有する棘の数の増加となることを示唆している。グルタミン酸アンケージング誘導性体性EPSC振幅は両群で類似であった(右側)。
(A)Camk2a−ニューロンにおけるmiR−128過剰発現が、マウスにおけるERK2リン酸化を抑制する。トランスジェニックCamk2a−cre;Rosa−miR−128突然変異体および対照マウス(それぞれn=4)の線条体中のERK2リン酸化レベルを、ウエスタンブロット法によって定量化し、全ERK2発現に正規化し、平均対照レベルに対して示した。代表的なブロットを示す。ウェルチのt検定、*p≦0.05。
(B)miR−128過剰発現が、マウスにおける化学的誘発反応亢進運動行動を減弱する。このスキームは、片側性6−OHDA誘発損傷を有する野生型マウスの標準的な回転反応を示している。6−OHDAおよびビヒクルをそれぞれ左線条体および右線条体に注射し、コカイン(ドーパミン作動性末端での内因性ドーパミン取り込みを阻害し、それによってシナプスドーパミンレベルを増加させる)またはDrd1−アゴニストSKF81297(ドーパミンD1受容体(Drd1)の特異的活性化)のいずれかに対する回転反応を3週間の回復期間後に評価する。コカイン注射は、機能的ドーパミン作動性末端をまだ含有する非損傷反対側線条体の強力な活性化による同側性(損傷側に向けた)回転を誘発する。Drd1−アゴニストSKF81297の注射は、損傷同側性線条体におけるドーパミン枯渇後のDrd1活性化に対するD1−ニューロンの異常な過敏性による反対側回転(損傷部位から離れる)を誘発する。
1.M.He et al.,Neuron 73,35(Jan 12,2012).2.N.Y.Shao et al.,BMC genomics 11,409(2010).3.E.A.Miska et al.,Genome biology 5,R68(2004).4.A.M.Krichevsky et al.,RNA 9,1274(Oct,2003).5.C.R.Gerfen.Annual review of neuroscience 15,285(1992).6.A.V.Kravitz et al.,Nature 466,622(Jul 29,2010).7.M.R.Fabian et al.Annual review of biochemistry 79,351(2010).8.A.Schaefer et al.,The Journal of experimental medicine 207,1843(Aug 30,2010).9.S.W.Chi.Nature 460,479(Jul 23,2009).10.D.P.Bartel,Cell 136,215(Jan 23,2009).11.M.Heiman et al.,Cell 135,738(Nov 14,2008).12.S.van Dongen et al.,Nature methods 5,1023(Dec,2008).13.A.Grimson et al.,Molecular cell 27,91(Jul 6,2007).14.J.G.Doench,Genes & development 18,504(Mar 1,2004).15.M.J.Brodie,Seizure:the journal of the British Epilepsy Association 19,650(Dec,2010).16.J.W.Ramos et al.,Molecular biology of the cell 11,2863(Sep,2000).17.A.Matsuda et al.,Oncogene 22,3307(May 22,2003).18.S.V.Rakhilin et al.,Science 306,698(Oct 22,2004).19.S.P.Megraw M et al.,Theor Chem Acc,593(2010).20.J.D.Sweatt,Current opinion in neurobiology 14,311(Jun,2004).
Claims (25)
- 脳内のmiR−128の発現および/または活性を増加させることができる薬剤の治療上有効量を個体に投与することを含む、てんかんを有する危険があるまたは有する疑いがある個体のてんかんまたはてんかん重積状態の発症を治療するまたはその可能性を減少させる方法。
- miR−128の発現および/または活性を増加させることができる薬剤の治療上有効量を個体に投与することを含む、発作の危険があるまたは発作を有する個体の発作の発症もしくは発生を治療するまたはその可能性を減少させる方法であって、ここで、前記患者が、発作の発症を特徴とする脳関連障害を有するものとする、前記方法。
- miR−128の発現および/または活性を増加させることができる薬剤の治療上有効量を個体に投与することを含む、てんかんを発症する危険がある個体のてんかんの発症を治療するまたはその可能性を減少させる方法であって、ここで、前記個体が、前記個体のてんかんのリスクを増加させる脳損傷を以前に患っているものとする、前記方法。
- 前記個体が、Dravet症候群を有する疑いがあるまたはDravet症候群と診断されている、請求項1、2または3に記載の方法。
- 前記薬剤が、くも膜下腔内または鼻腔内投与される、請求項1、2または3に記載の方法。
- 前記薬剤が、前記個体の中枢神経系に投与される、請求項1、2または3に記載の方法。
- 前記薬剤が、海馬または皮質に投与される、請求項1、2または3に記載の方法。
- 前記薬剤が、miR−128である、またはmiR−128と90%以上の配列同一性を有する薬剤である、請求項1、2または3に記載の方法。
- miR−128の発現および/または活性を増加させることができる前記薬剤が、化学的に安定化されたmiR−128、miR−128模倣物、miR−128をコードする核酸およびmiR−128をコードするウイルスベクターからなる群から選択される、請求項1、2または3に記載の方法。
- miR−128が、ヌクレオチド配列:UCACAGUGAACCGGUCUCUUUを有する、請求項9に記載の方法。
- miR−128の発現および/または活性を増加させることができる前記薬剤が、脳由来神経栄養因子である、請求項1、2または3に記載の方法。
- 発作の発症を特徴とする前記脳関連障害が、脳卒中、低酸素症、外傷性脳損傷、感染症、腫瘍、神経変性障害、発作を引き起こす代謝および自己免疫障害からなる群から選択される、請求項2に記載の方法。
- 前記脳損傷が脳卒中によって引き起こされる、請求項12に記載の方法。
- 薬学的に許容される賦形剤と組み合わせて、miR−128の発現または活性を増加させることができる薬剤を含む、発作を特徴とする神経病態の発症の治療またはその可能性の減少に使用するための医薬組成物。
- miR−128の発現または活性を増加させることができる前記薬剤が、化学的に安定化されたmiR−128、miR−128模倣物、miR−128をコードする核酸およびmiR−128をコードするウイルスベクターからなる群から選択される、請求項13に記載の組成物。
- miR−128が、ヌクレオチド配列:UCACAGUGAACCGGUCUCUUUを有する、請求項15に記載の組成物。
- 発作の危険がある個体の発作の可能性の減少において、またはてんかんを誘発しそうな脳損傷を有する個体における抗てんかん発生薬として使用するためのmiR−128の発現または活性を増加させることができる薬剤であって、前記個体の脳に送達される薬剤。
- miR−128発現細胞を候補化合物と接触させることと、前記細胞によって発現されている前記miR−128の発現および/または活性のレベルを測定することとを含む、発作を特徴とする病態の治療またはその可能性の減少に有用な化合物を同定する方法であって、ここで、前記候補化合物と接触していない細胞中のmiR−128の発現および/または活性の基準レベルに対する前記miR−128の発現および/または活性のレベルの増加が、前記候補化合物が発作を特徴とする病態の治療または予防に有用であることを示すものとする、前記方法。
- 発作を特徴とする前記病態が、てんかん、てんかん重積状態、脳卒中、低酸素症、外傷性脳損傷、感染症、腫瘍、神経変性障害、発作を引き起こす代謝および自己免疫障害を含む群から選択される、請求項18に記載の方法。
- 長さが6〜30ヌクレオチドの間のオリゴマーを含む薬剤を投与することを含む、哺乳動物細胞中のmiR−128の発現または活性を増加させる方法であって、ここで、前記オリゴマーが、miR−128の配列中に存在する少なくとも6個の隣接ヌクレオチドと同一である隣接ヌクレオチド配列を含むものとする、前記方法。
- インビトロで行われる、請求項20に記載の方法。
- インビボで行われる、請求項20に記載の方法。
- 前記オリゴマーが、miR−128のシード領域のヌクレオチド配列と同一である隣接ヌクレオチド配列を含む、請求項20に記載の方法。
- 前記オリゴマーが、miR−128のシード領域の配列と同一である隣接ヌクレオチド配列からなる、請求項20に記載の方法。
- 前記オリゴマーの前記隣接ヌクレオチド配列が、miR−128の対応する領域の配列と同一である7〜23個の間のヌクレオチドを含む、請求項20に記載の方法。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361896463P | 2013-10-28 | 2013-10-28 | |
US61/896,463 | 2013-10-28 | ||
US201361898952P | 2013-11-01 | 2013-11-01 | |
US61/898,952 | 2013-11-01 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016527396A Division JP6700180B2 (ja) | 2013-10-28 | 2014-10-28 | 神経興奮性および運動行動を調節するための組成物および方法 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2020158506A true JP2020158506A (ja) | 2020-10-01 |
JP2020158506A5 JP2020158506A5 (ja) | 2020-12-03 |
JP7014852B2 JP7014852B2 (ja) | 2022-02-01 |
Family
ID=53005028
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016527396A Active JP6700180B2 (ja) | 2013-10-28 | 2014-10-28 | 神経興奮性および運動行動を調節するための組成物および方法 |
JP2020079949A Active JP7014852B2 (ja) | 2013-10-28 | 2020-04-30 | 神経興奮性および運動行動を調節するための組成物および方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016527396A Active JP6700180B2 (ja) | 2013-10-28 | 2014-10-28 | 神経興奮性および運動行動を調節するための組成物および方法 |
Country Status (8)
Country | Link |
---|---|
US (3) | US10087443B2 (ja) |
EP (2) | EP3825402A1 (ja) |
JP (2) | JP6700180B2 (ja) |
AU (2) | AU2014342535B2 (ja) |
CA (1) | CA2929098A1 (ja) |
ES (1) | ES2836133T3 (ja) |
PL (1) | PL3074050T3 (ja) |
WO (1) | WO2015066034A1 (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101814868B1 (ko) * | 2015-06-18 | 2018-01-04 | 재단법인대구경북과학기술원 | 마이크로 rna와 nmda 수용체의 상관관계를 이용한 해마의 기능감소 판단 방법, 기능감소 억제 방법 및 기능감소 억제제 스크리닝 방법 |
JP6923509B2 (ja) * | 2015-07-28 | 2021-08-18 | オトノミ—,インク. | 切断型のtrkbおよびtrkcのアンタゴニストを使用する処置 |
CA3001594A1 (en) | 2015-10-14 | 2017-04-20 | Audentes Therapeutics, Inc. | Nucleic acid molecules containing spacers and methods of use thereof |
US11236337B2 (en) | 2016-11-01 | 2022-02-01 | The Research Foundation For The State University Of New York | 5-halouracil-modified microRNAs and their use in the treatment of cancer |
CN110290794A (zh) * | 2016-11-01 | 2019-09-27 | 纽约州州立大学研究基金会 | 5-卤代尿嘧啶修饰的微rna及其在癌症治疗中的用途 |
WO2019227255A1 (zh) * | 2018-05-26 | 2019-12-05 | 深圳市博奥康生物科技有限公司 | miRNA-128过表达载体的构建及其应用 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5830857A (en) * | 1995-07-14 | 1998-11-03 | Amgen Inc. | Method of treating epilepsy |
BR9712824A (pt) * | 1996-09-13 | 1999-12-21 | Advanced Medicine Research Ins | Composição oftálmica de fator neurotrófico, agente de tratamento de desordem funcional do nervo ótico e método para tratamento de desordem funcional do nervo ótico |
WO2006070292A2 (en) * | 2004-10-12 | 2006-07-06 | Queen's University At Kingston | Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents |
CA2850323A1 (en) * | 2004-11-12 | 2006-12-28 | Asuragen, Inc. | Methods and compositions involving mirna and mirna inhibitor molecules |
EP2623095A1 (en) * | 2004-11-16 | 2013-08-07 | Elan Pharma International Limited | Injectable nanoparticulate olanzapine formulations |
AU2009271524A1 (en) * | 2008-07-16 | 2010-01-21 | The Board Of Trustees Of The Leland Stanford Junior University | Modulation of GM98 (MRF) in remyelination |
CA2808372C (en) * | 2010-08-16 | 2021-11-16 | Brainstem Biotec Ltd. | Methods of generating oligodendrocytes and cell populations comprising same |
WO2012097261A2 (en) | 2011-01-14 | 2012-07-19 | The General Hospital Corporation | Methods targeting mir-128 for regulating cholesterol/lipid metabolism |
EP2761002B1 (en) | 2011-09-28 | 2021-11-17 | Royal College of Surgeons in Ireland | Inhibition of microrna-134 for the treatment of seizure-related disorders and neurologic injuries |
JP5850702B2 (ja) * | 2011-10-25 | 2016-02-03 | 国立大学法人岐阜大学 | 間葉系細胞の分化調節剤およびこれを用いた医薬、並びに間葉系細胞への分化調節作用を有する物質のスクリーニング方法 |
GB201223244D0 (en) | 2012-12-21 | 2013-02-06 | Ucb Pharma Gmbh | Micrornas as therapeutics and biomarkers for epilepsy |
US9434945B2 (en) | 2013-08-02 | 2016-09-06 | University Of Maryland, Baltimore | Use of miR-23a-3p and/or miR-27a-3p mimics as therapeutic agents for inhibition of neuronal apoptosis following brain injury |
CN103656685B (zh) | 2014-01-10 | 2016-01-13 | 厦门大学 | microRNA-219在制备抗癫痫药物中的应用 |
WO2015175965A1 (en) | 2014-05-15 | 2015-11-19 | The Research Foundation For Suny | Compositions targeting the interaction domain between p27kip1 and brk and methods of use thereof |
-
2014
- 2014-10-28 WO PCT/US2014/062664 patent/WO2015066034A1/en active Application Filing
- 2014-10-28 AU AU2014342535A patent/AU2014342535B2/en active Active
- 2014-10-28 PL PL14857152T patent/PL3074050T3/pl unknown
- 2014-10-28 ES ES14857152T patent/ES2836133T3/es active Active
- 2014-10-28 US US15/032,255 patent/US10087443B2/en active Active
- 2014-10-28 EP EP20194773.6A patent/EP3825402A1/en active Pending
- 2014-10-28 EP EP14857152.4A patent/EP3074050B1/en active Active
- 2014-10-28 JP JP2016527396A patent/JP6700180B2/ja active Active
- 2014-10-28 CA CA2929098A patent/CA2929098A1/en active Pending
-
2018
- 2018-10-01 US US16/148,015 patent/US10870853B2/en active Active
-
2020
- 2020-04-30 JP JP2020079949A patent/JP7014852B2/ja active Active
- 2020-07-01 AU AU2020204419A patent/AU2020204419B2/en active Active
- 2020-11-16 US US17/099,209 patent/US20210317451A1/en active Pending
Non-Patent Citations (2)
Title |
---|
CANCER. RES., vol. Vol.68(22), JPN6018023912, 2008, pages 9125 - 9130, ISSN: 0004520001 * |
近畿大学産業理工学部かやのもり, vol. 25, JPN6021020012, 2016, pages 1 - 6, ISSN: 0004520000 * |
Also Published As
Publication number | Publication date |
---|---|
JP2016540740A (ja) | 2016-12-28 |
US20160244757A1 (en) | 2016-08-25 |
US20210317451A1 (en) | 2021-10-14 |
US10870853B2 (en) | 2020-12-22 |
AU2014342535B2 (en) | 2020-04-02 |
EP3074050B1 (en) | 2020-09-09 |
US10087443B2 (en) | 2018-10-02 |
AU2014342535A1 (en) | 2016-06-09 |
AU2020204419A1 (en) | 2020-07-23 |
EP3074050A1 (en) | 2016-10-05 |
EP3825402A1 (en) | 2021-05-26 |
JP7014852B2 (ja) | 2022-02-01 |
AU2020204419B2 (en) | 2023-11-02 |
ES2836133T3 (es) | 2021-06-24 |
US20190144858A1 (en) | 2019-05-16 |
CA2929098A1 (en) | 2015-05-07 |
EP3074050A4 (en) | 2017-11-29 |
WO2015066034A1 (en) | 2015-05-07 |
JP6700180B2 (ja) | 2020-05-27 |
ES2836133T8 (es) | 2022-09-09 |
PL3074050T3 (pl) | 2021-04-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7014852B2 (ja) | 神経興奮性および運動行動を調節するための組成物および方法 | |
Sztainberg et al. | Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides | |
Chavali et al. | Small organelle, big responsibility: the role of centrosomes in development and disease | |
Brahmachari et al. | Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson’s disease | |
Kumar et al. | MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer's disease | |
JP6791877B2 (ja) | デュシェンヌ型筋ジストロフィーを治療するためのダイナミン2阻害剤 | |
Burbano et al. | Antisense oligonucleotide therapy for KCNT1 encephalopathy | |
EP3119406B1 (en) | Methods for improving cognitive function via modulation of quinone reductase 2 | |
WO2008157747A1 (en) | Use of inhibition of exonuclease 1 in methods for therapy and diagnostic of neurodegenerative diseases, eye diseases, and mitochondrial disorders | |
BR112021010793A2 (pt) | Métodos de detecção, prevenção, reversão e tratamento de doenças neurológicas | |
US20230293642A9 (en) | Treatment and detection of inherited neuropathies and associated disorders | |
Xi et al. | Gene augmentation prevents retinal degeneration in a CRISPR/Cas9-based mouse model of PRPF31 retinitis pigmentosa | |
WO2017201425A1 (en) | Anabolic enhancers for ameliorating neurodegeneration | |
US20170246200A1 (en) | Microrna-132/212 for the treatment of neurodegenerative disorders | |
US20200172927A1 (en) | Reprogramming metabolism by inhibiting vhl for treatment of neurodegeneration | |
Hwu et al. | AADC deficiency: occurring in humans, modeled in rodents | |
US20220305027A1 (en) | Methods of controlling and improving brain health | |
Lagali et al. | Retinal interneuron survival requires non-cell-autonomous Atrx activity | |
CN115006534A (zh) | 钾离子通道Kir4.1抑制剂治疗抑郁症的用途和药物组合物 | |
Ning | Biological mechanisms underlying susceptibility to traumatic stress: evidence from rodent models | |
US20230203497A1 (en) | Dynamin 2 inhibitor for the treatment of centronuclear myopathies | |
Keidar | The effects of LIS1 and MeCP2 reduced dosage in the mouse brain | |
Stringer | The Identification of Increased DYRK1A Protein Levels in TS65DN Mice Guides the Targeted Adminstration of the Novel DYRK1A Inhibitor CX-4945 | |
Ferreira | Establishing the relevance of Tau isoform imbalance in the onset and progression of Machado-Joseph disease | |
Zanetti et al. | GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200601 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200716 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201019 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210601 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210830 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20210924 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20211022 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211201 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20211228 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20220120 |