CN105106222A - Application of tormentic acid in preparation of medicine for treating or preventing Alzheimer disease caused by estrogen lack - Google Patents
Application of tormentic acid in preparation of medicine for treating or preventing Alzheimer disease caused by estrogen lack Download PDFInfo
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- VULLSLYDWNGNKZ-UHFFFAOYSA-N 12319Tetrahydroxyurs-12-en-28-oic acid Natural products OC1C(O)C(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)C(O)(C)C5C4=CCC3C21C VULLSLYDWNGNKZ-UHFFFAOYSA-N 0.000 title claims abstract description 74
- OXVUXGFZHDKYLS-UHFFFAOYSA-N Jacarandic acid Natural products C1C(O)C(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)C(O)(C)C5C4=CCC3C21C OXVUXGFZHDKYLS-UHFFFAOYSA-N 0.000 title claims abstract description 74
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses application of tormentic acid in preparation of medicine for treating or preventing the Alzheimer disease caused by estrogen lack, and belongs to the technical field of tormentic acid medicine new application. According to the technical scheme, the application is characterized in that the molecular formula of the tormentic acid is C30H48O5, and the structural formula is as shown in specifications; the tormentic acid can improve the cognition impairment of an AD patient and increase the number of in-brain cholinergic neurons and has a neuron protection effect on CNS, wherein the protection effect can be achieved through ERalpha, and the result provides experimental bases for using the tormentic acid as a medicine select for treating menopause women in combination with AD.
Description
Technical field
The invention belongs to the new medical use technical field of tormentic acid, be specifically related to the application of a kind of tormentic acid in the Alzheimer disease drugs that preparation is treated or prevention estrogen deficiency causes.
Background technology
Alzheimer (Alzheimer ' sDisease, AD) be common neural degenerative disease, show as the deposition of senile plaque, Progressive symmetric erythrokeratodermia ability of learning and memory is lost and the hypophrenia.The main component of senile plaque is beta-amyloid polypeptide 1-(beta-amyloid, A β).Research report, in female patient blood, estrogen level reduces with AD clinical symptoms closely related.Estrogen not only has the effect of regulation and control reproduction and body development, also has and reduces excitatory amino acid release, neuroprotective and improve the functions such as learning and memory.Epidemiology shows, and AD is a kind of disease having gender tendency, and the sickness rate of old women is apparently higher than elderly men, and prompting estrogen deficiency, at AD, tool significance in evolution occurs.
Extensively there is estrogen receptor (Estrogenreceptors, ER) in brain, research finds that estrogen receptor such as ER α, ER β etc. can regulate the nerve excitability of Hippocampus and the ability of learning and memory based on Hippocampus.Meanwhile, the quantity of the learning and memory extent of damage and cholinergic neuron is closely related.Therefore, the content improving acetylcholine in brain is an extraordinary strategy for the treatment of AD.
Tormentic acid is a kind of triterpenoid saponin material, can extract from the leaf of Fructus Fragariae Ananssae fruit, Folium Perillae and Fructus Canarii albi etc.Research finds, the inflammatory reaction of the microglia that tormentic acid energy antagonism LPS-induces.Suppress propagation and the survival of smooth muscle cell.Tormentic acid can suppress hyperlipemia and the fulminant hepatic failure of sciatic pathological pain and high fat diet induction.
Controversies in hormone replacement in the elderly is own to be affirmed, but still disputable as the long-term prescription of safety, if increase abnormal vaginal bleeding and the risk increasing breast carcinoma etc.We adopt ovariectomized mice, as object of study, to illustrating tormentic acid, estrogen receptor and the function of nervous system mutual relation in AD morbidity, specify tormentic acid to estrogen receptor and to the effect in nervous system, for the treatment of the AD disease caused after clinical estrogen deficiency provides theoretical foundation.
Summary of the invention
The technical problem that the present invention solves there is provided the application of a kind of tormentic acid in the Alzheimer disease drugs that preparation is treated or prevention estrogen deficiency causes.
Technical scheme of the present invention is, the application of tormentic acid in the Alzheimer disease drugs that preparation is treated or prevention estrogen deficiency causes, wherein the molecular formula of tormentic acid is C
30h
48o
5, structural formula is:
。
Further restriction, described medicine is made up of tormentic acid and pharmaceutically acceptable carrier or excipient.
Tormentic acid of the present invention merges the application in Alzheimer disease drugs in preparation treatment or prevention menopausal women, wherein the molecular formula of tormentic acid is C
30h
48o
5, structural formula is:
。
Further restriction, described medicine is made up of tormentic acid and pharmaceutically acceptable carrier or excipient.
Tormentic acid of the present invention can improve the cognitive dysfunction of AD patient; improve the quantity of brain Cholinergic Neurons; to CNS, there is neuroprotective; this protective effect can realize by ER α, and this result is that the medicament selection that tormentic acid merges AD as treatment menopausal women provides experimental basis.
Accompanying drawing explanation
Fig. 1 is that the present invention respectively organizes mice Meynert core group ChAT positive neuron Immunohistochemical detection figure;
Fig. 2 is the Westernblot detection figure that the present invention respectively organizes hippocampus of mice ER α and ER β protein expression.
Detailed description of the invention
Be described in further details foregoing of the present invention by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment
1 materials and methods
1.1 modelings and grouping
Oophorectomize Model of Dementia mice modeling: select C57BL mouse, 3 monthly ages, body weight (30 ± 2) g.With pentobarbital sodium (0.25mL/100g) the intraperitoneal anesthesia mice that mass concentration is 1.5%, skin more than sterilization preserved skin pubis, along side skin 2cm on medisection pubis, open abdomen muscle layer also opens abdominal cavity, be separated respectively and expose bilateral pink ovary, ligation also extracts bilateral ovaries (ovariectomy, OVX), suture muscles and skin successively, postoperative iodophor disinfection.Sham operated rats only exposes ovary.Within postoperative 3rd day, carry out vaginal smear, within continuous 7 days, occur that upper foreskin keratinocytes then proves oophorectomize success.Oophorectomize Model of Dementia is the nervous system disease caused due to estrogen deficiency, and the oophorectomize Model of Dementia time needs 6-8 week.
Tormentic acid is Hubei Ju Sheng Science and Technology Ltd. product, its molecular formula: C
30h
48o
5, structural formula:
。
Adult female mice is divided into four groups at random, i.e. sham operated rats, OVX group, OVX+ tormentic acid treatment group and OVX+ carrier dummy treatment group.Tormentic acid treatment group carries out gavage treatment with 30mg/kg, and every two days once, treats 8 weeks.The ability of learning and memory of Morris water maze test mice is carried out after 8 weeks.Then put to death mice, be separated Hippocampus, measure the change of corresponding index.
1.2Morris water maze determination experiment
The tank of Morris water maze video analytic system is made up of the round pool of diameter 120cm, high 55cm, black inwall, depth of water 41cm, water temperature 24 ± 2 DEG C, and pool wall is divided into 4 quadrants, and escape platform and be positioned at one of them quadrant, platform is lower than water surface 1cm.Peripheral pool object of reference remains unchanged as space with reference to clue.Path of animal movement is by the camera system collection above labyrinth.Morris water maze laboratory program comprises: (1) constant-bearing navigation is tested: experiment lasts 5d, and every day at the upper and lower noon carries out.From a quadrant, successively mice is put into water from all quadrants edge, be recorded in 60s and find the time escaping platform to be incubation period.(2) space exploration experiment: remove escape platform, mice is put into water by an optional place of entry, in record 60s, mice passes through the number of times escaping platform.
the experimental procedure that 1.3ELISA detects
By the Hippocampus cerebral tissue position homogenate of each group of mice, after guanidine hydrochloride (Tris-HCL, pH=8.0 containing the 50mM) homogenate of homogenate: 5M-70 DEG C frozen to be measured.During mensuration, melt sample, in 1.5mL centrifuge tube 4 DEG C, 12000 × g, centrifugal 30min, get supernatant 50 μ L, measures Hippocampus A β 40 level by ELISA kit description method.ELISA kit is purchased from BioSource company (BioSourceInternational, Inc., Camarillo, California).
(1) dilution of standard substance: require the A β 1-40 standard substance of Mus to be diluted to following concentration to specifications: 500pg/mL, 250pg/mL, 125pg/mL, 62.5pg/mL, 31.25pg/mL, 15.63pg/mL, 7.81pg/mL, 0pg/mL.
(2) application of sample: set up blank control wells, gauge orifice and sample to be tested hole.Blank control wells adds sample diluting liquid 100 μ L, and other holes add standard substance or each 100 μ L of sample to be tested, and 37 DEG C, 120min, abandons liquid.
(3) add A working solution 100 μ L, 37 DEG C, 60min, discards.
(4) rinsing: add cleaning mixture 350 μ L, rinsing 3min × 3 time.
(5) B working solution 100 μ L is added, 37 DEG C, 60min.
(6) rinsing: add wash operating solution 350 μ L, 3min × 5 time.
(7) develop the color: add substrate 90 μ L, 37 DEG C of lucifuges hatch 30min, reactant liquor gradually becomes blue.
(8) stop: add stop buffer 50 μ L cessation reaction, now reactant liquor becomes yellow.
(9) reading: microplate reader measures the optical density (OD value) in each hole at 450nm wavelength.
(10) A β 1-40 concentration is calculated according to standard curve and the OD value recorded.
1.4 immunohistochemical stainings detect choline second phthalein transferring enzyme neuron:
Fix with the paraformaldehyde perfusion that mass concentration is 4% after mouse anesthesia, fixing after getting cerebral tissue, saccharose gradient dehydration, embedding, freezing microtome is made continuous coronal section, thick 20 μm of sheet.The plane of similarity that every animal of each group of mice gets Meynert basal nuclei cuts into slices 5, and add rabbit anti-mouse ChAT primary antibodie, 4 DEG C of refrigerators hatch 24h, and PBS cleans 3 times, adds anti-rabbit two and resists, hatch 2h for 37 DEG C.Often open section Stochastic choice 5 visuals field, count all ChAT positive cell numbers in the Meynert basal nuclei visual field respectively.
1.5 superoxide dismutase (SuperoxideDismutase, SOD) vitality tests:
SOD test kit is purchased from the green skies company in Shanghai, and operating procedure is as follows:
(1) preparation of NBT/ enzyme working solution: detect buffer, 1 μ LNBT and 1 μ L enzymatic solution according to each reaction 160 μ L(158 μ LSOD), 4 DEG C or ice bath preservation.
(2) reaction starts the preparation of working solution: the reaction primer fluid (40X) in test kit is melted rear mixing, and every 1 μ L reaction primer fluid (40X) adds 39 μ LSOD detection buffer and dilutes, 4 DEG C of preservations.(3) SOD standard substance prepare: SOD standard substance are diluted to following concentration by the diluent provided with test kit: 200U/mL, 100U/mL, 50U/mL, 20U/mL, 10U/mL, 5U/mL, 2U/mL.In detection subsequently, respectively get 20 μ L, reference sample detects.Absorbance is measured at 560nm.SOD vigor=(control tube OD value-measure pipe OD value)/control tube OD value × (reactant liquor cumulative volume/sampling amount)/protein content.
1.6 protein immunoblots (Westernblot)
Chloral hydrate anesthesia mice, breaking end and divesting meninges exposes cerebral tissue.Fritter in the bearing of anatomic microscope mirror and get hippocampal tissue 50mg.Rapidly tissue is placed in protein lysate (10mMHEPESpH=7.5, the 1.5mMMgCl containing protease inhibitor of pre-cooling
2, 10mMKCl, 1mMEDTA, 1mMDTT, mass concentration 10%glycerol, 1mMPMSF, 1 × protease inhibitor).30min is placed in homogenate on ice.100 DEG C of water-bath 5min.Cooled on ice 5min, 4 DEG C, 12000 × g, centrifugal 30min.Get supernatant, BCA method surveys concentration, and subpackage, saves backup in-80 DEG C.Through mass concentration be 5% concentrated glue and mass concentration be 10% separation gel electrophoresis, then electricity goes on pvdf membrane, mass concentration be 5% defatted milk powder close, add primary antibodie (anti-PKC-α (the Millipore company of rabbit respectively, the U.S.) 4 DEG C of overnight incubation, TBST rinsing 10min × 3 time, add HRP labelling two and resist, incubated at room 2h.TBST rinsing 10min × 3 time.ECL is luminous, development, fixing, with α-tubulin(Millipore company, and the U.S.) carry out gray scale quantitative analysis as internal reference.
1.7 statistical procedures
Experimental data mean ± standard deviation (
± s) represent, carry out statistical analysis with SPSS13.0 statistical software, compare between group and check with t.The variance analysis of escape latency completely randomized design and the multifactor analysis of variance of repeated measurement data; The variance analysis of space exploration test completely randomized design.
p< 0.05 has statistical significance for difference.
2 results
2.1 tormentic acids are on the impact of oophorectomize Model of Dementia ability of learning and memory in mice
Result of study shows: oophorectomize group compares with sham operated rats, and the escape latency of mice obviously extends, and crosses over platform number of times and obviously reduces,
p< 0.05, after showing oophorectomize, estrogen deficiency Model of Dementia modeling success.After last Drug therapy, Morris water maze test is carried out to mice, detect the change of mice Spatial memory ability.Result shows: in incipient training, and mice is mainly travelling along water maze edge finds platform, show as search platform randomness and without purposiveness.Along with the increase of training, the mice of oophorectomize group still keeps this search strategy, and the behavior of tormentic acid treatment group animal search platform has tendentiousness and purposiveness, and some animals are directly swum to escape platform according to memory.Group in result of calculation show, time factor have remarkable statistical significance (
p< 0.05).Statistical result showed between group, has remarkable statistical significance (table 1) between tormentic acid treatment group and carrier dummy treatment group.
In space exploration test, analyze the number of times (table 2) of mice spanning platform in 60s.Result shows: tormentic acid treatment group mice carries out around original platform quadrant and position of platform, and carrier dummy treatment group mice still moves about along pool wall; Spanning platform number of times is added up, result show: tormentic acid treatment group than dummy treatment group showed increased, difference have remarkable statistical significance (
p< 0.05).
Table 1 each group mice Morris water maze escape latency (
± s, n=5, second)
| Group | Second |
| Sham operated rats | 35.73±7.67 |
| OVX group | 49.66±8.12* |
| OVX+ tormentic acid treatment group | 36.43±6.98 |
| OVX+ carrier dummy treatment group | 50.04±8.09# |
Note: OVX group compares with sham operated rats, *
p< 0.05; OVX+ tormentic acid treatment group compares with OVX+ carrier dummy treatment group, #
p< 0.05.
Table 2 each group mice Morris water maze spanning platform number of times (
± s, n=5, secondary)
| Group | Number of times |
| Sham operated rats | 6.45±1.22 |
| OVX group | 4.12±1.43* |
| OVX+ tormentic acid treatment group | 6.23±1.38 |
| OVX+ carrier dummy treatment group | 4.09±1.42# |
Note: OVX group compares with sham operated rats, *
p< 0.05; OVX+ tormentic acid treatment group compares with OVX+ carrier dummy treatment group, #
p< 0.05.
2.2 tormentic acids are on the impact of oophorectomize Model of Dementia hippocampus of mice A β 40 level
ELISA result shows, and A β 40 expression of oophorectomize Model of Dementia group Hippocampus and the obvious rising of sham operated rats, difference has significance statistical significance
p< 0.05, shows that OVX can cause Hippocampus A β 40 protein expression level to raise; And after tormentic acid treatment, A β 40 expression of tormentic acid treatment group hippocampus of mice and the obvious reduction of carrier dummy treatment group,
p< 0.05, difference has statistical significance, shows that tormentic acid can reduce the protein expression level (table 3) of Hippocampus A β 40.
Table 3 respectively group hippocampus of mice A β 40 expression (
± s, n=5, %)
| Group | % |
| Sham operated rats | 100.00±10.42 |
| OVX group | 126.60±16.09 |
| OVX+ tormentic acid treatment group | 104.60±9.67 |
| OVX+ carrier dummy treatment group | 126.58±16.08 |
Note: OVX group compares with sham operated rats, *
p< 0.05; OVX+ tormentic acid treatment group compares with OVX+ carrier dummy treatment group, #
p< 0.05.
2.3 tormentic acids affect oophorectomize Model of Dementia mice Meynert core ChAT neuron number object
Compared with sham operated rats, in oophorectomize group mouse brain, the ChAT positive neuron number of Septum Medialis obviously reduces, and difference has statistical significance.Tormentic acid treatment group compares with carrier dummy treatment group, and the ChAT positive neuron number of tormentic acid treatment group mice significantly increases.The treatment of prompting tormentic acid can reverse ChAT neuron number minimizing (Fig. 1, table 4) that removal ovary causes.
Table 4 each group hippocampus of mice Meynert core ChAT neuron number (
± s, n=5, individual)
| Group | Individual |
| Sham operated rats | 10.50±1.33 |
| OVX group | 7.09±0.91* |
| OVX+ tormentic acid treatment group | 9.88±1.45 |
| OVX+ carrier dummy treatment group | 7.08±0.90# |
Note: OVX group compares with sham operated rats, *
p< 0.05; OVX+ tormentic acid treatment group compares with OVX+ carrier dummy treatment group, #
p< 0.05.
2.4 tormentic acids are on the impact of oophorectomize Model of Dementia hippocampus of mice SOD activity
We show experimental result: OVX group hippocampus of mice SOD is active obviously to be reduced, and compare with sham operated rats, difference has statistical significance,
p< 0.05, illustrates that the estrogen deficiency that spay causes can cause hippocampus of mice SOD activity to reduce; SOD activity and the obvious rising of carrier dummy treatment group of OVX+ tormentic acid treatment group hippocampus of mice, difference has statistical significance,
p< 0.05, illustrates that tormentic acid can make hippocampus of ovariectomized mouse SOD activity raise (table 5).
Table 5 each group hippocampus of mice SOD activity (
± s, n=5, U/mgprotein)
| Group | U/mg protein |
| Sham operated rats | 65.46±6.03 |
| OVX group | 50.91±6.05* |
| OVX+ tormentic acid treatment group | 64.75±7.10 |
| OVX+ carrier dummy treatment group | 50.80±5.99# |
Note: OVX group compares with sham operated rats, *
p< 0.05; OVX+ tormentic acid treatment group compares with OVX+ carrier dummy treatment group, #
p< 0.05.
2.5 tormentic acids are on the impact of oophorectomize Model of Dementia hippocampus of mice ER α and ER β protein expression
Each group of hippocampus of mice ER α westernblot result display, the ER alpha expression level of oophorectomize group Hippocampus and the obvious reduction of sham operated rats,
p< 0.05, difference has significance statistical significance, shows that OVX can cause ER α protein expression to decline.But the ER β expression of oophorectomize group Hippocampus compares without obviously changing with sham operated rats, no significant difference statistical significance
p> 0.05; Tormentic acid group: hippocampus of mice ER alpha expression level and the obvious raising of carrier dummy treatment group,
p< 0.05, difference has statistical significance, shows that tormentic acid can raise Hippocampus ER α protein expression level.But the ER β expression of tormentic acid group and carrier dummy treatment group is without obvious change, no significant difference,
p> 0.05(Fig. 2, table 6).
Table 6 respectively group hippocampus of mice ER α protein expression level (
± s, n=5, relative value)
| Group | ER α relative value | ER β relative value |
| Sham operated rats | 1.00±0.10 | 1.00±0.10 |
| OVX group | 0.79±0.11* | 0.97±0.11 |
| OVX+ tormentic acid treatment group | 1.02±0.18 | 0.92±0.13 |
| OVX+ carrier dummy treatment group | 0.78±0.10# | 0.98±0.10 |
Note: OVX group compares with sham operated rats, *
p< 0.05, OVX+ tormentic acid treatment group compares with OVX+ carrier dummy treatment group, #
p< 0.05.
Clinically, there is the probability of AD disease apparently higher than male in 65 years old later women.After mice spay, change and the menopausal women estrogen of its estrogen level change similar, and oophorectomize is a kind of estrogen deficiency animal model preferably.Research display, the ability of learning and memory of oophorectomize animal after 8 weeks declines.This experiment changes with the behavioristics of Morris determined with Morris water animal and tormentic acid affects it.We show result: oophorectomize is after 8 weeks, the escape latency of OVX group mice obviously extends, spanning platform number of times significantly reduces, compare with Sham-operated control group and have significant difference, oophorectomize Model of Dementia modeling success is described, the estrogen deficiency that oophorectomize causes can cause ability of learning and memory to reduce; And escape latency obvious shortening compared with carrier dummy treatment group of OVX+ tormentic acid group mice, traversing times increases, and difference has statistical significance, illustrate ovariectomized mouse adopt tormentic acid treatment after, ability of learning and memory be improved significantly.
The typical pathological features of AD shows as ECS A β and deposits.After A beta peptide aggregation, toxicity is produced, by causing the response to oxidative stress induced neuronal death of cell to neuron.Zooscopy points out long-term estrogen deficiency can increase A β positive neuron quantity in Hippocampus.And Long-term Oral Low Dose Estrogen contributes to preventing A β in OVX rat hippocampus structure from depositing increase.This research prepares estrogen deficiency dementia rats model by spay, found that, OVX group compares with sham operated rats, A β 40 expression of OVX group hippocampus of mice obviously raises, difference has remarkable statistical significance, illustrate that estrogen deficiency can cause A β in Hippocampus to generate and increase, AD symptom is aggravated.And with after tormentic acid treatment; OVX+ tormentic acid treatment group compares with OVX+ carrier dummy treatment group; the A β 40 of OVX+ tormentic acid treatment group hippocampus of mice expresses and reduces, and illustrates that the A β that tormentic acid can reduce in estrogen deficiency Model of Dementia brain deposits, thus realizes the effect of protection cerebral tissue.
Meynert basal nuclei cholinergic neuron sends Fiber Projections to Hippocampus and cerebral cortex, and the ACh of release plays an important role to cognitive activities.ChAT synthesizes in cholinergic neuron cell space, is the distinctive mark of cholinergic neuron.This experiment utilizes ChAT antibody labeling cholinergic neuron, and after observing oophorectomize, the change of Meynert basal nuclei cholinergic neuron and tormentic acid treatment affect it.Result shows: OVX group Meynert basal nuclei cholinergic neuron compares with sham operated rats, and ChAT positive neuron quantity obviously reduces, and causes estrogen deficiency that cholinergic neurons of basal forebrain can be caused to reduce after spay is described; And OVX+ tormentic acid group mice Meynert basal nuclei cholinergic neuron compares with carrier dummy treatment group, ChAT positive neuron quantity showed increased, applies the loss that tormentic acid treatment can reverse cholinergic neurons of basal forebrain after showing removal ovary.
SOD is very important antioxidase in body, can remove superoxide anion, and energy Cell protection, from oxidative damage, plays balanced action to body internal oxidition and antioxidation process, is the important indicator of reflection body Scavenging ability.This experimental result shows: OVX group Hippocampus SOD is active obviously to be reduced, and compares and has significant difference, illustrate that spay causes estrogen deficiency that body Scavenging ability can be caused to reduce with sham operated rats; OVX+ tormentic acid treatment group compares Hippocampus SOD activity with carrier dummy treatment group obviously raises, and difference has statistical significance, and the oxygen-derived free radicals after can reducing removal ovary after the treatment of application tormentic acid in Hippocampus produces, and reduces nerve cell death or loss thus.
Estrogen mainly synthesizes in ovary and testis, and sub-fraction acts on distal tissues synthesis by androgen aromatization, except regulation and control reproductive system, also plays protective effect to cardiovascular and cerebrovascular vessel and central nervous system.Estrogen is combined with ER and forms hormone-receptor complex and activate ER, the specific estrogen response element effect on ER and the DNA be activated, thus regulates destination gene expression.ER has two kinds of configurations: ER α is mainly distributed in uterus, Placenta Hominis, mammary gland, cardiovascular system, central nervous system are unified in osseous tissue, and these tissues can induce estradiol response element to express; ER β is mainly distributed in prostate, testis, thyroid, pinus, parathyroid gland, skin, urethra and erythrocyte, and in these tissues, ER β expresses seldom.In AD risk factor, the minimizing of estrogen level and estrogen receptor is that minority can one of interference factor, and the relation specifying estrogen receptor and AD has important clinical meaning.This experimental result shows; OVX causes Dementia in Rats and estrogen receptor ER alpha levels to reduce; Hippocampus ER β expresses no difference of science of statistics; prompting ER α is more subject to the adjustment of endogenous estrogen level than ER β; ER alpha expression reduces and neuron can be caused to accept estrogenic protective effect weaken, thus causes neuronal degeneration or death.After giving tormentic acid treatment, the hippocampus ER alpha expression of mice significantly improves, and ER β expresses without significance change, and these results prompting tormentic acid plays a role mainly through ER α.Tormentic acid may become the ideal medicament improving postmenopausal women after date cognitive dysfunction.
In a word; tormentic acid can improve the cognitive dysfunction of AD patient, improves the quantity of brain Cholinergic Neurons, has neuroprotective to CNS; this protective effect can realize by ER α, and this result is that the medicament selection that tormentic acid merges AD as treatment menopausal women provides experimental basis.
Embodiment above describes ultimate principle of the present invention, principal character and advantage; the technical staff of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and description just illustrates principle of the present invention; under the scope not departing from the principle of the invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the scope of protection of the invention.
Claims (4)
1. the application of tormentic acid in the Alzheimer disease drugs that preparation is treated or prevention estrogen deficiency causes, wherein the molecular formula of tormentic acid is C
30h
48o
5, structural formula is:
。
2. the application of tormentic acid according to claim 1 in preparation treatment or the Alzheimer disease drugs that causes of prevention estrogen deficiency, is characterized in that: described medicine is made up of tormentic acid and pharmaceutically acceptable carrier or excipient.
3. tormentic acid merges the application in Alzheimer disease drugs in preparation treatment or prevention menopausal women, and wherein the molecular formula of tormentic acid is C
30h
48o
5, structural formula is:
。
4. tormentic acid according to claim 3 merges the application in Alzheimer disease drugs in preparation treatment or prevention menopausal women, it is characterized in that: described medicine is made up of tormentic acid and pharmaceutically acceptable carrier or excipient.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011461A (en) * | 2007-02-08 | 2007-08-08 | 广州中医药大学 | Rabdosia serra (Maxim.) hara extract, preparing process and application thereof |
| CN101073574A (en) * | 2006-05-17 | 2007-11-21 | 罗河生 | Medicine for treating diabetes mellitus |
| EP2425832A1 (en) * | 2010-09-03 | 2012-03-07 | China Medical University | Tormentic acid for the treatment of skin disorders |
| CN102391347A (en) * | 2011-08-09 | 2012-03-28 | 南京泽朗医药科技有限公司 | Joint preparation method for euscaphic acid and tormentic acid |
| CN103623082A (en) * | 2013-11-29 | 2014-03-12 | 江西中医药大学 | Raspberry extract and application thereof |
| CN102548571B (en) * | 2009-06-12 | 2014-08-27 | 基因雷克斯制药有限公司 | Compositions and methods for prevention and treatment of brain diseases and conditions |
-
2015
- 2015-09-14 CN CN201510581200.5A patent/CN105106222B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101073574A (en) * | 2006-05-17 | 2007-11-21 | 罗河生 | Medicine for treating diabetes mellitus |
| CN101011461A (en) * | 2007-02-08 | 2007-08-08 | 广州中医药大学 | Rabdosia serra (Maxim.) hara extract, preparing process and application thereof |
| CN102548571B (en) * | 2009-06-12 | 2014-08-27 | 基因雷克斯制药有限公司 | Compositions and methods for prevention and treatment of brain diseases and conditions |
| EP2425832A1 (en) * | 2010-09-03 | 2012-03-07 | China Medical University | Tormentic acid for the treatment of skin disorders |
| CN102391347A (en) * | 2011-08-09 | 2012-03-28 | 南京泽朗医药科技有限公司 | Joint preparation method for euscaphic acid and tormentic acid |
| CN103623082A (en) * | 2013-11-29 | 2014-03-12 | 江西中医药大学 | Raspberry extract and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| A. MA等: "TORMENTIC ACID REDUCES INFLAMMATION IN BV-2 MICROGLIA BY ACTIVATING THE LIVER X RECEPTOR ALPHA", 《NEUROSCIENCE》 * |
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