CN102657644A - Use of nocardamine in preparation of senile dementia-resisting drug - Google Patents
Use of nocardamine in preparation of senile dementia-resisting drug Download PDFInfo
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- CN102657644A CN102657644A CN2012100954472A CN201210095447A CN102657644A CN 102657644 A CN102657644 A CN 102657644A CN 2012100954472 A CN2012100954472 A CN 2012100954472A CN 201210095447 A CN201210095447 A CN 201210095447A CN 102657644 A CN102657644 A CN 102657644A
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- senile dementia
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- nocardamine
- promise card
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Abstract
The invention discloses a use of nocardamine in preparation of a senile dementia-resisting drug. An experiment proves that nocardamine has obvious improvement effects on memory and space exploration capacities of mice as models of senile dementia caused by A beta 25-35, improves determination of the activity of choline acetyltransferase in a cortex and hippocampus, has obvious improvement effects on memory and space exploration capacities of rats as models of senile dementia caused by D-galactose and AlCl3, improves the activity of an SOD enzyme and reduces the damage of radicals on brain tissue. Therefore, nocardamine has obvious effects of resisting senile dementia, can be used for preparation of senile dementia-resisting drugs and has good market prospects in clinical senile dementia-resisting drug development.
Description
Technical field
The present invention relates to the application of promise card amine (Nocardamine) in the preparation anti senile dementia drug.
Background technology
Senile dementia is one group of constitutional degeneration brain degenerative disease that the cause of disease is not bright.A lot of diseases are in the geratic period, and the course of disease is slow and irreversible, are main with the intelligence infringement clinically, and chronic and persistence obstacle takes place function to show as memory, orientation, language, judgement, cognition and be intended to etc.Along with the arrival of global aged tendency of population, its number of the infected constantly increases; China has a large population, and is the higher country of senile dementia sickness rate, so the research and development of anti senile dementia drug are particularly urgent.
Promise card amine (Nocardamine) is peptide hydroxyl oxime compound, is by 3 succinic acid and 3 33 yuan of cyclic compounds that N-hydroxyl pentanediamine forms with the form polymerization of peptide bond, and contains 3 hydroxyl oxime structures in the molecule, and molecular formula is C
27H
48N
6O
9It is reported that this chemical compound has antibacterial activity, especially the activity of tetracycline resistance Resistant strain can also induce the form of insecticide BM-N4 cell to change etc. in addition.
This chemical compound can by
StreptomycesSp. 211726,
Streptomyces hygroscopicusVar
.geldanus,
Pseudomonas stutzeriProduce etc. multiple actinomycete fermentation; Simultaneously also can be according to document Keller-Schierlein W, Prelog V.
Helv Chim Acta, 1962,45:590-595. or patent (US3118823) method through the chemosynthesis preparation, more can directly be bought acquisition from market.
Summary of the invention
The purpose of this invention is to provide the application of promise card amine (Nocardamine) in the preparation anti senile dementia drug.
The molecular structure of promise card amine (Nocardamine) is following among the present invention:
, chemistry is by name, and 1,12,23-trihydroxy-1,6,12,17,23,28-hexaazacyclotritriacontane-2,5,13,16,24,27-hexone.
Promise card amine of the present invention (Nocardamine) can be bought by commerce and obtain, and also can be obtained by multiple actinomycetes strain fermenting process of preparing, also can prepare through synthetic method.
The present invention passes through A β
25～35Due to the determination of activity of choline acetyltransterase in Morris water maze training test and cortex thereof, the hippocampal tissue of senile dementia model mice; Proof promise card amine has significant improvement effect to senile dementia mouse memory and space exploration ability; So can be used for preparing anti senile dementia drug; And when dosage was big, its effect was superior to the positive control drug piracetam.
The present invention passes through D-galactose and AlCl
3Due to the determination of activity of SOD enzyme in the training test of Morris water maze and the serum thereof of Senile Dementia Model Rats; Prove that also promise card amine has significant improvement effect to memory of senile dementia rat and space exploration ability; And the activity of ability enhancement of SOD enzyme; Alleviate the radical pair brain tissue injury, when dosage was big, its effect also was superior to the positive control drug piracetam.
The present invention selects classical senile dementia animal modeling method for use; Copy senile dementia model mice and rat; And give the promise card amine intervention of animal pattern various dose respectively, all show: promise card amine has significant anti-senile dementia effect, can be applicable to prepare anti senile dementia drug.Also show in addition: when the dosage of promise card amine is that 30 mg/kg are when above; Its enhancing aspect to the improvement of model mice, rat memory and SOD, ChAT enzymatic activity all is superior to positive control drug piracetam group, shows its good prospect of marketing as clinical anti senile dementia drug.
The specific embodiment
Embodiment 1:
1.1 laboratory animal and reagent
Laboratory animal: 60 of cleaning level healthy male Kunming mouses, body weight 26～30 g purchase the Experimental Animal Center in Nanfang Medical Univ.
Reagent: promise card amine (Nocardamine) is purchased the company in German Genaxxon BioScience GmbH; A β
25～35Purchase company in Sigma; ChAT enzymatic determination test kit is purchased and is built up bio-engineering research institute in Nanjing; Piracetam is purchased in Hubei Huahzong Medicine Co., Ltd.
1.2 condensed state A β
25～35Preparation
With 2 mg A β
25～35Be dissolved in the 2 mL sterile salines, concentration is 1 mmol/L.Sealing is placed in 37 ℃ of cell culture incubators hatches 96 h, makes it become the A β of condensed state
25～35, be placed in 4 ℃ of refrigerators subsequent use.
1.3 mice AD Preparation of model and administration
Mice with etherization after, the excision bilateral ovaries.Perform the operation behind 10 d, mice is divided into matched group, A β at random
25～35Group, A β
25～35+ promise card amine group
IWith A β
25～35+ promise card amine group
II, 10 every group.Control group mice intracerebroventricular injection normal saline.Other group mice intracerebroventricular injection 1 mmol/L A β
25～355 μ L prepare the AD mouse model.After model prepares 7 d, matched group and A β
25 ~ 35Group mouse peritoneal injecting normal saline 5 mL/kg; A β
25～35+ promise card amine group
IWith A β
25～35+ promise card amine group
IIThe group mouse peritoneal is injected promise card amine 10 mg/kg, 30 mg/kg, continuous use 14 d respectively.
1.4 training of Morris water maze and test
The training of self administration of medication beginning in the 8th day water maze, totally 7 d.Special water maze platform is put in the 4th quadrant, and every mice detects 2 times every day, gets rid of platform place quadrant, adherently in the centre of other 3 quadrants puts into mice.No longer descend water to think that once test accomplishes with mice 10 s that appear on the stage; Full 90 s of mice record that can not appear on the stage, and the guiding mice makes it on platform, continue 30 s, to enforce one's memory to platform.Photograph the swimming process of mice, write down for 1 week altogether, this is the learning process of mice.Learning process finishes 1 week of back, removes platform, the space exploration ability of test mice.
1.5 the active mensuration of choline acetyltransterase in experiment mice cortex and the hippocampal tissue (ChAT enzyme)
The mice broken end is got brain, on ice bath, separate cortex and hippocampal tissue, place liquid nitrogen freezing after weighing rapidly.Add kaliumphosphate buffer 50 mmol/L of pre-cooling afterwards, ice bath is processed 10% tissue homogenate, adopts ChAT enzymatic determination test kit, to specifications, and the activity of ChAT enzyme in determination experiment mouse cortex and the hippocampal tissue.
1.6 statistical analysis
Experimental result with
± s representes, adopts SPSS 11.0 software kits to carry out variance analysis, uses
tThe comparison between each group is carried out in check.
1.7 result and conclusion
As positive control, measure the influence of promise card amine to experiment mice space exploration ability with piracetam, its result's (table 1) shows: the promise card amine of lumbar injection 10 mg/kg, 30 mg/kg all can shorten A β
25～35Due to the senile dementia model mice incubation period, increased the platform number of times, and prolong in first quartile residence time.Compare with model group, all have significant difference; Compare with positive control piracetam group, lumbar injection 30 mg/kg promise card amine have significant difference.Show that promise card amine is to A β
25～35Due to the memory and the behavior of senile dementia model mice have the tangible effect of improving, wherein the effect of improving of lumbar injection 30 mg/kg promise card amine is superior to the positive control drug piracetam.
[0019] table 1 promise card amine to the influence of experiment mice space exploration ability (
n=15)
| Group | Dosage/mgkg -1 | Incubation period/s | Cross platform number of times/inferior | t 1Account for t AlwaysPercentage ratio/t 1/t Always |
| Matched group | - | 22.65±3.72 | 3.68±0.86 | 32.56±1.31 |
| Aβ 25～35Group | - | 68.17±13.39 | 0.49±0.51 | 14.92±1.96 |
| Aβ 25～35 + piracetam group | 400 | 29.23±3.25 | 2.97±0.92 | 27.85±1.17 |
| Aβ 25～35 + promise card amine group I | 10 | 26.58±3.32 ** | 3.12±0.57 ** | 26.95±1.83 ** |
| Aβ 25～35 + promise card amine group II | 30 | 21.76±3.77 **## | 4.78±0.86 **## | 35.48±1.32 **## |
Annotate: with A β
25 ~ 35Group compares,
* P＜0.05,
* P＜0.01; With A β
25 ~ 35+ piracetam group compares:
# P＜0.05,
## P＜0.01.
Simultaneously, measure choline acetyl transfers enzyme activity in above-mentioned experiment mice cortex and the hippocampal tissue, its result's (table 2) shows: with A β
25～35Group (model group) and positive control piracetam group compare, and lumbar injection 10 mg/kg, 30 mg/kg promise card amine all have significant difference, show that promise card amine can significantly strengthen A β
25～35Due to the activity of choline acetyltransterase in senile dementia model mice cortex and the hippocampal tissue, thereby improve the learning and memory function of senile dementia.
Table 2 promise card amine to the influence of choline acetyl transfers enzyme activity in mouse cortex and the hippocampal tissue (
n=15)
| Group | Dosage/mgkg -1 | Choline acetyltransterase vigor/Ug -1 |
| Matched group | - | 108.39±0.91 |
| Aβ 25～35Group | - | 55.26±0.83 |
| Aβ 25～35 + piracetam group | 400 | 105.69±0.85 |
| Aβ 25～35 + promise card amine group I | 10 | 101.27±0.91 **## |
| Aβ 25～35 + promise card amine group II | 30 | 121.32±1.24 **## |
Annotate: with A β
25 ~ 35Group compares,
* P＜0.05,
* P＜0.01; With A β
25 ~ 35+ piracetam group compares:
# P＜0.05,
## P＜0.01.
All show with analyzing in sum: promise card amine is to A β
25～35Due to the having significant anti-senile dementia effect and improve memory function of senile dementia model mice, so can be used for preparing anti senile dementia drug, and show that it has applications well and DEVELOPMENT PROSPECT aspect preparation anti senile dementia drug.
Embodiment 2
2.1 laboratory animal and reagent
Laboratory animal: aged healthy male Wistar rat, body weight 350～390 g, purchase the Experimental Animal Center in Nanfang Medical Univ by totally 60.
Reagent: promise card amine (Nocardamine) is purchased the company in German Genaxxon BioScience GmbH; D-galactose, AlCl
3Purchase in Chemical Reagent Co., Ltd., Sinopharm Group; The SOD enzyme reagent kit is purchased and is built up bio-engineering research institute in Nanjing; Piracetam is purchased in Hubei Huahzong Medicine Co., Ltd.
2.2 the preparation of compound senile dementia animal model and administration
The Wistar rat be will test and matched group, model group, promise card amine group will be divided at random
I, promise card amine group
II, 15 every group.The model group abdominal cavity gives D-galactose 60 mg/kg (normal saline preparation) and orally give AlCl
35mg/kg (distilled water preparation); Promise card amine group I and group II remove to adopt identical route of administration to give D-galactose and AlCl with the model group same dose
3Outward, simultaneously also respectively lumbar injection give promise card amine 20 mg/kg, 40 mg/kg (normal saline preparation).Successive administration 90 d.
2.3 training of Morris water maze and test
Self administration of medication the 83rd d begins according to instance 1 method, the water maze of the rat that experimentizes training, totally 7 d.Learning process finishes 1 week of back, removes platform, the space exploration ability of test rat.
2.4 the mensuration of SOD enzymatic activity in the experimental rat serum
After accomplishing the water maze test, get 10 rats for every group, after chloral hydrate anesthesia, open breast fast, in the heart blood sampling, get serum behind centrifugal 10 min of 3500 r.p.m, put-70 ℃ of low-temperature preservations.Press the test kit description, adopt determined by ultraviolet spectrophotometry respectively to organize the activity of SOD enzyme in the experimental rat serum.
2.5 statistical analysis
Experimental result is represented with ± s, adopts SPSS 11.0 software kits to carry out variance analysis, uses
tThe comparison between each group is carried out in check.
2.6 result and conclusion
As positive control, measure the influence of promise card amine to experimental rat space exploration ability with piracetam, its result's (table 3) shows: the promise card amine of lumbar injection 20 mg/kg, 40 mg/kg all can shorten D-galactose and AlCl
3Due to Senile Dementia Model Rats incubation period, increased the platform number of times, and prolong in first quartile residence time.Compare with model group, all have significant difference; Compare with positive control piracetam group, lumbar injection 40 mg/kg promise card amine have significant difference.Show that promise card amine is to D-galactose and AlCl
3Due to the memory and the behavior of Senile Dementia Model Rats have the tangible effect of improving, wherein the effect of improving of lumbar injection 40 mg/kg promise card amine is superior to the positive control drug piracetam.
Table 3 promise card amine to the influence of experimental rat space exploration ability (
n=15)
| Group | Dosage/gkg -1 | Incubation period/s | Cross platform number of times/inferior | t 1Account for t AlwaysPercentage ratio/t 1/t Always |
| Matched group | - | 22.95±3.32 | 3.45±0.51 | 32.59±1.27 |
| Model group | - | 63.17±2.71 | 0.79±0.41 | 15.96±1.83 |
| The piracetam group | 400 | 27.72±3.79 | 3.05±0.35 | 27.92±1.25 |
| Promise card amine group I | 20 | 27.19±3.28 ** | 3.01±0.42 ** | 26.05±1.35 ** |
| Promise card amine group II | 40 | 20.17±3.26 **## | 4.92±0.88 **## | 37.18±1.12 **## |
Annotate: compare with model group,
* P＜0.05,
* P＜0.01; Compare with the piracetam group:
# P＜0.05,
## P＜0.01.
Simultaneously; Measure the activity of SOD enzyme in the above-mentioned experimental rat serum; Its result's (table 4) shows: compare with model group and positive control piracetam group, lumbar injection 20 mg/kg, 40 mg/kg promise card amine all have significant difference, show that promise card amine can significantly strengthen D-galactose and AlCl
3Due to the activity of SOD enzyme in the Senile Dementia Model Rats serum, alleviate the radical pair brain tissue injury, protection brain cell and tissue.
Table 4 promise card amine to the influence of SOD enzymatic activity in the experimental rat serum (
n=10)
| Group | Dosage/gkg -1 | SOD/U·mL -1 |
| Matched group | - | 93.57±1.72 |
| Model group | - | 71.62±1.39 |
| The piracetam group | 400 | 91.38±1.65 |
| Promise card amine group I | 20 | 92.32±1.41 ** |
| Promise card amine group II | 40 | 108.16±1.78 **## |
Annotate: compare with model group,
* P＜0.05,
* P＜0.01; Compare with the piracetam group:
# P＜0.05,
## P＜0.01.
All show with analyzing in sum: promise card amine is to D-galactose and AlCl
3Due to Senile Dementia Model Rats have significant anti-senile dementia effect and improve memory function; Further proof promise card amine can be used for preparing anti senile dementia drug, also shows that it has applications well and DEVELOPMENT PROSPECT aspect preparation anti senile dementia drug simultaneously.
Claims (1)
1. the application of promise card amine in the preparation anti senile dementia drug.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106955351A (en) * | 2016-01-08 | 2017-07-18 | 周艳玲 | A kind of pharmaceutical composition of anti-senile dementia |
Citations (2)
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|---|---|---|---|---|
| US3118823A (en) * | 1960-11-24 | 1964-01-21 | Ciba Geigy Corp | Method for producing ferrioxamine |
| JP2001247556A (en) * | 2000-03-03 | 2001-09-11 | Marine Biotechnol Inst Co Ltd | New siderophore activator produced by marine bacterium and method of producing the same |
-
2012
- 2012-04-01 CN CN 201210095447 patent/CN102657644B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3118823A (en) * | 1960-11-24 | 1964-01-21 | Ciba Geigy Corp | Method for producing ferrioxamine |
| JP2001247556A (en) * | 2000-03-03 | 2001-09-11 | Marine Biotechnol Inst Co Ltd | New siderophore activator produced by marine bacterium and method of producing the same |
Non-Patent Citations (8)
| Title |
|---|
| 《Neuroscience Research》 20071231 Minji Kim,et al Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models S1-S244 1 第58S卷, * |
| 《PLOS ONE》 20100401 Spilman P,et al Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer"s disease 摘要 1 第5卷, 第3期 * |
| 《中国海洋药物杂志》 20100831 袁干军，等 海洋链霉菌211726 代谢产物的研究 7-10 1 第29 卷, 第4 期 * |
| 《植物保护》 20111231 曾庆飞，等 根结线虫拮抗放线菌的筛选及菌株ＨＡ１０００２的鉴定与活性物质分析 159-163 1 第37卷, 第6期 * |
| MINJI KIM,ET AL: "Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models", 《NEUROSCIENCE RESEARCH》, vol. 58, 31 December 2007 (2007-12-31), pages 1 - 244 * |
| SPILMAN P,ET AL: "Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer"s disease", 《PLOS ONE》, vol. 5, no. 3, 1 April 2010 (2010-04-01) * |
| 曾庆飞，等: "根结线虫拮抗放线菌的筛选及菌株ＨＡ１０００２的鉴定与活性物质分析", 《植物保护》, vol. 37, no. 6, 31 December 2011 (2011-12-31), pages 159 - 163 * |
| 袁干军，等: "海洋链霉菌211726 代谢产物的研究", 《中国海洋药物杂志》, vol. 29, no. 4, 31 August 2010 (2010-08-31), pages 7 - 10 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106955351A (en) * | 2016-01-08 | 2017-07-18 | 周艳玲 | A kind of pharmaceutical composition of anti-senile dementia |
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