CN117159531A - Application of bronzolamide sodium in preparing medicine for preventing and treating senile dementia - Google Patents
Application of bronzolamide sodium in preparing medicine for preventing and treating senile dementia Download PDFInfo
- Publication number
- CN117159531A CN117159531A CN202310937933.2A CN202310937933A CN117159531A CN 117159531 A CN117159531 A CN 117159531A CN 202310937933 A CN202310937933 A CN 202310937933A CN 117159531 A CN117159531 A CN 117159531A
- Authority
- CN
- China
- Prior art keywords
- group
- rats
- cell
- bzp
- senile dementia
- 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.)
- Pending
Links
- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 40
- 206010039966 Senile dementia Diseases 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 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 title claims abstract description 9
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 9
- 239000011734 sodium Substances 0.000 title claims abstract description 9
- 229940079593 drug Drugs 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- -1 α -hydroxypentyl Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000007972 injectable composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 16
- 238000002474 experimental method Methods 0.000 abstract description 13
- 206010012289 Dementia Diseases 0.000 abstract description 9
- 230000005779 cell damage Effects 0.000 abstract description 6
- 208000037887 cell injury Diseases 0.000 abstract description 6
- 238000001727 in vivo Methods 0.000 abstract description 4
- 238000012404 In vitro experiment Methods 0.000 abstract description 3
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 abstract 1
- 229960000722 brinzolamide Drugs 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 56
- 210000004027 cell Anatomy 0.000 description 49
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 21
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 19
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 19
- 201000004810 Vascular dementia Diseases 0.000 description 18
- 108090001005 Interleukin-6 Proteins 0.000 description 17
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000002757 inflammatory effect Effects 0.000 description 8
- 230000003833 cell viability Effects 0.000 description 6
- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical class C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 5
- 231100000318 excitotoxic Toxicity 0.000 description 5
- 230000003492 excitotoxic effect Effects 0.000 description 5
- 210000001320 hippocampus Anatomy 0.000 description 5
- 108010063738 Interleukins Proteins 0.000 description 4
- 102000015696 Interleukins Human genes 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 210000000225 synapse Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 210000000805 cytoplasm Anatomy 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 230000013016 learning Effects 0.000 description 3
- 230000006386 memory function Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000004904 shortening Methods 0.000 description 3
- 206010003694 Atrophy Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 210000004295 hippocampal neuron Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000009182 swimming Effects 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- 102000003390 tumor necrosis factor Human genes 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010065384 Cerebral hypoperfusion Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000010826 Nissl staining Methods 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000006933 amyloid-beta aggregation Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 230000008809 cell oxidative stress Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 210000001947 dentate gyrus Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004693 neuron damage Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to application of the pharmaceutical composition in preparation of a medicine for treating senile dementia. Relates to the application of the brinzolamide in treating senile dementia. The invention establishes a dementia model of a dementia rat and a mouse through in-vivo experiments; in vitro experiments establish a PC12 cell, BV2 cell and HT22 cell injury model, and the bronzolamide sodium has the effect of preventing and treating senile dementia. Is expected to be clinically applied to preparing the medicine for treating senile dementia.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, relates to a pharmaceutical application of bronzolamide sodium, and in particular relates to an application of bronzolamide sodium in preparing a medicine for treating senile dementia.
Background
Sodium Bromozoprate (BZP), also known as Sodium 5-Bromo-2- (α -hydroxypentyl) benzoate, has the following molecular structural formula:
which is an analogue of butylphthalide (NBP), a drug for treating cerebral ischemia. The research team of the invention discovers that BZP has good prevention and treatment effects on senile dementia for the first time.
With the increase of the aging problem, the occurrence rate of senile dementia has increased year by year, and senile dementia is classified into primary dementia and vascular dementia (vascular dementia, VD), the former being also called Alzheimer's Disease (AD). The formation of amyloid plaques and neurofibrillary tangles by aβ deposition are the main pathological features of AD, and clinical conditions are manifested by dysmnesia, mental retardation, impaired motor balance, severe changes in mood and personality, loss of life self-care ability and even death. Vascular dementia, which is the most common dementia after primary dementia, accounts for 20% -30% of total dementia, is a symptom of brain cell damage, neuronal death, and dementia in turn caused by various cerebrovascular diseases such as cerebral infarction, cerebral hemorrhage, cerebral hypoperfusion, etc., and is manifested by progressive cognitive decline, mood disorder, and difficulty in language and daily life. However, the clinical medicines for treating the senile dementia are very limited, and the development of new medicines for preventing and treating the senile dementia is urgently needed at present.
Disclosure of Invention
The invention synthesizes 5-bromo-2- (alpha-hydroxypentyl) sodium benzoate by earlier work of a research team, and obtains patent authorization, and long-term research shows that the sodium benzoate has good effect of preventing and treating ischemic cerebral apoplexy.
In order to achieve the purpose of the invention, the technical scheme is as follows:
the invention establishes a dementia model of a dementia rat and a mouse through in-vivo experiments; in vitro experiments establish a PC12 cell, BV2 cell and HT22 cell injury model, and prove that the brizopran sodium has the effects of preventing and treating senile dementia.
The invention has the advantages that: according to the invention, in vitro and in vivo experiments show that BZP can improve the learning, memory and cognitive functions of VD rats and AD rats by shortening the average incubation period of rats, increasing the crossing times of rats in target quadrants and prolonging the effective time of the rats in target quadrants. In addition, BZP was found to significantly increase the cell survival rate and improve cell morphology following L-Glu-induced PC12 cell excitotoxic cell injury. Wherein 20. Mu. Mol/L BZP group had better effect on improving cell viability than the equimolar NBP group (P < 0.05). Is expected to be used for preparing the medicine for treating senile dementia and applied clinically.
Drawings
Figure 1 is a schematic of eight weeks post 2-VO surgery, after four weeks of dosing each group of rats were subjected to the last water maze test, a: incubation period of Vascular Dementia (VD) rats of each group from day 58 to 62 after 2-VO surgery; b: the number of times that VD rats of each group traversed the target quadrant on day 62 after 2-VO surgery; c: effective time of stay of each group of rats in target quadrant on day 62 after 2-VO operation; d: swim trace graphs of VD rats in each group on day 62 after 2-VO surgery; * P＜0.05， ** p <0.01 compared to the Sham group; # P＜0.05， ## p <0.01 is compared with the group 2-VO. (mean ± standard deviation, n=10-12).
Fig. 2 is a final water maze test performed on groups of rats four weeks after administration at the same time point, a: incubation period of AD rats in each group at day 58-62 of the same time point; b: the number of times each group of AD rats traversed the target quadrant on day 62; c: the effective time for each group of AD rats to stay in the target quadrant on day 62; d: swim trace for AD rats of each group on day 62; * P＜0.05， ** p <0.01 compared with the Control group; # P＜0.05， ## p <0.01 compared to AD group. (mean ± standard deviation, n=10-12).
Fig. 3 is the effect of BZP on VD rat hippocampal neurons (n=3).
Fig. 4 is the effect of BZP on AD rat hippocampal neurons (n=3).
FIG. 5 shows the effect of BZP on IL-6 and COX-2 inflammatory factor levels in peripheral blood plasma of VD rats, (A) IL-6; (B) COX-2. ** P<0.01 in comparison with the Sham group, # P<0.01, ## P<0.01 compared to the 2-VO group (mean ± standard deviation, n=5).
FIG. 6 shows the effect of BZP on cell morphology and cell viability following L-Glu induced PC12 cell excitotoxic injury. PC12 cells were then each incubated in complete medium containing BZP (10, 20, 40. Mu. Mol/L) for 18h and then injured with 20mM L-Glu-low-sugar DMEM for 24h. ** P<0.05 in contrast to the Control group, ## P<0.01 in comparison with the L-Glu group, ▲ P<0.05 compared to NBP group (FlatMean ± standard deviation, n=3).
FIG. 7 is a diagram of BZP versus H 2 O 2 Effect of induced oxidative stress on HT22 cells on cell morphology and cell viability. HT22 cells were incubated with BZP (10, 20, 40. Mu. Mol/L) in complete medium for 18H, followed by 400. Mu.M H 2 O 2 Low sugar DMEM lesion for 24h.
FIG. 8 shows the effect of BZP on IL-1β, IL-6, COX-2 and TNF- α inflammatory factor expression following L-Glu induced PC12 cell excitotoxic injury, (A) IL-1β; (B) IL-6; (C) COX-2; (D) TNF- α. ** P<0.01 in comparison with the Control group, ## P<0.01 compared to the L-Glu group (mean ± standard deviation, n=3). FIG. 9 shows the effect of BZP on LPS-induced expression of inflammatory factors of BV2 cells IL-1β, IL-6, COX-2 and TNF- α, (A) IL-1β; (B) IL-6; (C) COX-2; (D) TNF- α. * P<0.05, ** P<0.01 in comparison with the Control group, # P<0.05, ## P<0.01 compared to the LPS group (mean ± standard deviation, n=3).
Detailed Description
The NBP of the present invention is Ding Bentai, and for better illustrating the present invention, examples are as follows: example 1
1. In vivo experiments:
1. water maze behavioural experiment
1.1A modified bilateral common carotid artery (2-VO) procedure was used to establish a VD rat model. And screening the VD rats by using a first water maze, and observing the improvement effect of BZP on the behavior of the VD rats by using a last water maze test. The water maze was used to examine rat behaviours including: the average latency of each group of rats in the navigation experiment and the space exploration experiment and the number of times each group of rats crosses the target quadrant and the effective time of stay in the target quadrant in the space exploration experiment are positioned. The results are shown in FIG. 1.
From fig. 1, it can be seen that the average escape latency of each group of rats tended to shorten with the increase in training days. The average escape latency of rats in the 2-VO group was significantly prolonged (P < 0.01) compared to Sham group from day 58 to day 62 of the experiment; compared with the 2-VO group, the BZP (12, 24 mg/kg) group can obviously shorten the average escape latency period of rats (P <0.05, P < 0.01). On day 62, the effect of BZP (24 mg/kg) on shortening the mean escape latency of rats was significantly better than that of the equimolar dose NBP group (P < 0.05). As shown in FIG. 1B, the number of times of crossing the target quadrant is obviously reduced (P < 0.01) for the rats in the 2-VO group compared with the Sham group; the BZP (12, 24 mg/kg) group increased the number of crossing of the target quadrant (P < 0.05) in rats dose-dependently compared to the 2-VO group. As shown in FIG. 1C, the effective time for 2-VO group rats to stay in the target quadrant is significantly shortened (P < 0.05) compared to the Sham group; the BZP (12, 24 mg/kg) group dose-dependently prolonged the effective time (P < 0.05) of stay in the target quadrant for rats compared to the 2-VO group. As shown in the swim trace diagram of the rat in fig. 1D, compared with the Sham group, the effective time of the 2-VO group rat staying in the target quadrant and the number of times of crossing the target quadrant are obviously reduced, and the swim trace shows obvious marginality; compared with the 2-VO group, the residence time of BZP (12, 24 mg/kg) in the target quadrant and the crossing frequency of the target quadrant are increased in a dose-dependent manner, and the swimming track shows a certain purpose.
1.2 Primary AD mice in aged rats were screened using the first water maze, and the last water maze test observed the improvement effect of BZP on AD rat behaviours. The water maze was used to examine rat behaviours including: the average latency of each group of rats in the navigation experiment and the space exploration experiment and the number of times each group of rats crosses the target quadrant and the effective time of stay in the target quadrant in the space exploration experiment are positioned. The results are shown in FIG. 2.
From fig. 2, it can be seen that the average escape latency of each group of rats tended to shorten with the increase in training days. Compared with the Control group, the average escape latency of the rats in the AD group is obviously prolonged (P < 0.01) from the 58 th day to the 62 th day of the experiment; compared with the AD group, the BZP (12, 24 mg/kg) group can obviously shorten the average escape latency period (P <0.05 and P < 0.01) of rats. As shown in FIG. 2B, the number of times the rats of the AD group cross the target quadrant is obviously reduced (P < 0.01) compared with the Control group; the BZP (12, 24 mg/kg) group increased the number of crossing of the target quadrant (P < 0.05) in rats dose-dependently compared to the AD group. As shown in fig. 2C, the effective time for AD group rats to stay in the target quadrant is significantly shortened (P < 0.05) compared to Control group; in comparison to the AD group, the BZP (12, 24 mg/kg) group dose-dependently prolonged the effective time (P < 0.05) for which rats remained in the target quadrant. As shown in the swim trace diagram of the rat in fig. 2D, compared with the Control group, the effective time of the rat in the AD group staying in the target quadrant and the number of times of crossing the target quadrant are obviously reduced, and the swim trace shows obvious marginality; compared with the AD group, the residence time and the crossing frequency of the BZP (12, 24 mg/kg) group in the target quadrant are increased in a dose-dependent manner, and the swimming track shows a certain purpose.
The results demonstrate that BZP can improve learning, memory and cognitive function in VD rats, AD rats by shortening the average incubation period of the rats, increasing the number of times the rats cross the target quadrant and extending the effective time to stay in the target quadrant.
Nissl staining to detect changes in the morphology of the CA1, CA3, DG regions and neuronal number in the hippocampus of VD and AD rats
Nib is one of the characteristic structures of neuronal cytoplasm, and the density and color of Nib staining in neuronal cytoplasm can be used to evaluate the damage condition of neurons. The rat hippocampus mainly comprises CA1, CA3 and DG regions, wherein the CA1 and CA3 regions of the hippocampus are closely related to learning and memory functions, the DG region is also a dentate gyrus region of the hippocampus, is a region related to memory formation, exploration, stress and depression, is a key part of the hippocampus in connection with the outside, and is very important for coding spatial information.
As shown in FIGS. 3A, B and C, the CA1 region and CA3 region of the Sham group have compact cell arrangement, deep cytoplasmic color and conical DG region, and regular morphology; compared with a Sham group, the 2-VO group has serious neuronal damage in CA1 region, CA3 region and DG region, the cells are in sparse form, and the number of Nib bodies is obviously reduced; compared with the 2-VO group, the CA1 region of the BZP (12, 24 mg/kg) group has orderly and orderly recovered CA3 cells, the number of Nib bodies is obviously increased, and the DG region has a conical shape and a regular shape.
As shown in FIGS. 4A, B and C, the CA1 region and the CA3 region of the Control group are closely arranged, the cytoplasm is darker, and the DG region is conical and regular in shape; compared with the Control group, the CA1 region, CA3 region and DG region of the AD group have serious neuron damage, cells are in a sparse form, and the number of Nib bodies is obviously reduced; compared with the AD group, the CA1 region of the BZP (12, 24 mg/kg) group has orderly and orderly recovered CA3 cells, the number of Nib bodies is obviously increased, and the DG region has a conical shape and a regular shape.
Assay of inflammatory factors IL-6 and COX-2 in peripheral blood plasma of VD rats
The content of IL-6 and COX-2 in the peripheral blood plasma of VD rats is quantitatively detected by ELISA method. As shown in FIGS. 5A, B, the IL-6 and COX-2 content was elevated in the 2-VO group (P < 0.01) compared to the Sham group; while BZP (12, 24 mg/kg) group can reduce the content of IL-6 and COX-2 in blood plasma in a dose-dependent manner (P <0.05, P < 0.01) compared with the 2-VO group.
2. In vitro experiments
Effect of BZP on cell morphology and cell viability following L-Glu-induced PC12 cell excitotoxic cell injury
The morphology of each group of PC12 cells was observed after the group administration treatment and the survival rate of each group of PC12 cells was calculated: the form of each group of cells under the inverted microscope is shown in FIG. 6A, and the PC12 cells of the Control group are complete in form and orderly and tightly arranged; the number of PC12 cells induced by L-Glu is greatly reduced, more cell fragments are generated, cells show atrophy-like changes, synapses are retracted, and the arrangement is irregular; the BZP10, 20 and 40 mu mol/L groups and the NBP pre-incubation group improve the morphology of PC12 cells to different degrees, the cell bodies are full, the outline is clear, and the synapses and the cell number are obviously increased compared with the L-Glu group. Meanwhile, the survival rate of each group of cells is detected by a CCK8 method, and the result is that the survival rate of PC12 cells of the L-Glu group is greatly reduced (P < 0.01) compared with that of the Control group as shown in FIG. 6B; BZP at 10,20 and 40. Mu. Mol/L can increase cell viability in a concentration-dependent manner (P < 0.01) compared to the L-Glu group. The results demonstrate that BZP can significantly increase cell viability and improve cell morphology, with 20. Mu. Mol/L BZP group having better effect on cell viability than the equimolar NBP group (P < 0.05).
BZP vs. H 2 O 2 Influence of cell morphology following induced HT22 cell oxidative stress cell injury
Following the group dosing treatment, the HT22 cell morphology of each group was observed: the morphology of each cell group under the inverted microscope is shown in FIG. 7, and HT22 cells of the Control group are complete and alignedTightly; warp H 2 O 2 The number of HT22 cells after induction is greatly reduced, more cell fragments are generated, the cells show atrophy-like changes, the synapses are retracted, and the arrangement is irregular; BZP10, 20 and 40. Mu. Mol/L groups and NBP preincubation groups all improved the morphology of HT22 cells to a different extent, the cells were full, the contours were clear, and the synapses and cell numbers were higher than those of H 2 O 2 The group increased significantly.
BZP inhibits the expression of inflammatory factors associated with L-Glu-induced PC12 cell excitotoxic injury
Subsequent inflammatory reactions are secondary to the induction of L-Glu by PC12 cells, which are manifested by an increase in the secretion of inflammatory cytokines Interleukin (IL) -1 beta, IL-6, cyclooxygenase 2 (COX-2) and tumor necrosis factor (TNF-alpha) by PC12 cells.
As shown in FIGS. 8A, B, C, D, the L-Glu group IL-1β, IL-6, COX-2 and TNF- α expression was up-regulated (P < 0.01) compared to the Control group; whereas the 10,20, 40. Mu. Mol/L BZP group down-regulates cell IL-1β, IL-6, COX-2 and TNF- α expression (P <0.05, P < 0.01) in comparison with the L-Glu group, the 20. Mu. Mol/LBZP group down-regulates IL-1β, IL-6, COX-2 and TNF- α more than the NBP group (P < 0.01).
BZP inhibits LPS-induced expression of BV2 cell postrelative inflammatory factors
LPS can chemotactic BV2 cells into M1 type inflammation models in vitro. M1-type inflammatory cytokines mainly include Interleukin (IL) -1β, IL-6, cyclooxygenase 2 (COX-2), and tumor necrosis factor (TNF- α).
As shown in FIGS. 9A, B, C, D, the expression of IL-1β, IL-6, COX-2 and TNF- α was up-regulated in LPS groups (P <0.05, P < 0.01) compared to Control groups; whereas the 10,20, 40. Mu. Mol/L BZP group down-regulates the IL-1β, IL-6, COX-2 and TNF- α expression of cells in a concentration-dependent manner (P <0.05, P < 0.01) compared to the LPS group.
The BZP is expected to be clinically applied to preparing the medicine for treating the senile dementia.
Claims (2)
1. The medicine application of the 5-bromo-2- (alpha-hydroxypentyl) sodium benzoate with the following molecular structural formula is characterized in that the sodium benzoate is used as an active ingredient in the preparation of medicines for treating or preventing senile dementia,
。
2. the pharmaceutical use of sodium 5-bromo-2- (α -hydroxypentyl) benzoate according to claim 1, characterized in that it is formulated as an oral or injectable formulation with pharmaceutical excipients.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310937933.2A CN117159531A (en) | 2023-07-28 | 2023-07-28 | Application of bronzolamide sodium in preparing medicine for preventing and treating senile dementia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310937933.2A CN117159531A (en) | 2023-07-28 | 2023-07-28 | Application of bronzolamide sodium in preparing medicine for preventing and treating senile dementia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117159531A true CN117159531A (en) | 2023-12-05 |
Family
ID=88936514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310937933.2A Pending CN117159531A (en) | 2023-07-28 | 2023-07-28 | Application of bronzolamide sodium in preparing medicine for preventing and treating senile dementia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117159531A (en) |
-
2023
- 2023-07-28 CN CN202310937933.2A patent/CN117159531A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Thakur et al. | Pathophysiology and management of Alzheimer’s disease: An overview | |
| Ye et al. | β-Sitosterol treatment attenuates cognitive deficits and prevents amyloid plaque deposition in amyloid protein precursor/presenilin 1 mice | |
| EP2272515A1 (en) | Novel uses of sodium 4-phenylbutyrate (4 pba) and the pharmaceutically acceptable salts thereof | |
| Richardson et al. | Behavioural and histopathological analyses of ibuprofen treatment on the effect of aggregated Aβ (1–42) injections in the rat | |
| Zhang et al. | Icariin enhances remyelination process after acute demyelination induced by cuprizone exposure | |
| Qiao et al. | New insights in drug development for Alzheimer's disease based on microglia function | |
| KR102259791B1 (en) | Pharmaceutical composition for preventing or treating the dementia comprising human neural crest derived stem cells and screening method thereof | |
| Saeedi et al. | Challenges and approaches of drugs such as memantine, donepezil, rivastigmine, and aducanumab in the treatment, control and management of Alzheimer's disease | |
| Han et al. | Class I HDAC inhibitor improves synaptic proteins and repairs cytoskeleton through regulating synapse-related genes in vitro and in vivo | |
| JP2020523342A (en) | Compositions and methods for the inhibition of beta secretase | |
| CN100515428C (en) | Application of Li2WO4 in preparing medicine | |
| CN117159531A (en) | Application of bronzolamide sodium in preparing medicine for preventing and treating senile dementia | |
| CN103860575A (en) | Application of geniposide used as acetylcholin esterase inhibitor | |
| Sorenson et al. | Transient amnestic syndrome after spontaneous haemorrhage into a hypothalamic pilocytic astrocytoma. | |
| Wang et al. | Effects of curcumin on hippocampal Bax and Bcl-2 expression and cognitive function of a rat model of Alzheimer's disease*☆ | |
| Lozupone et al. | The challenge of antidepressant therapeutics in Alzheimer’s disease | |
| CN104415025B (en) | Composition for delaying progress of degenerative disease | |
| CN106361736A (en) | Application of guanidino compound | |
| US20220105106A1 (en) | Compositions and methods relating to use of agonists of alpha5-containing gabaa receptors | |
| CN108635358B (en) | Application of aspirin eugenol ester in preparation of medicine for preventing or treating Alzheimer disease | |
| Mirshekar et al. | The ameliorative effects of myricetin on neurobehavioral activity, electrophysiology, and biochemical changes in an animal model of traumatic brain injury | |
| CN113116934A (en) | Application of maggot for treating senile dementia | |
| Scorza et al. | Adult hippocampal neurogenesis and sudden unexpected death in epilepsy: Reality or just an attractive history? | |
| Fang et al. | AdipoRon Engages Microglia to Antinociception through the AdipoR1/AMPK Pathway in SNI Mice | |
| TWI587860B (en) | Use of quinoline derivatives for manufacturing pharmaceutical composition of tau-associated disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |