CN102144999A - Application of senkyunolide H in preparing medicine for preventing and curing cerebral apoplexy - Google Patents
Application of senkyunolide H in preparing medicine for preventing and curing cerebral apoplexy Download PDFInfo
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- CN102144999A CN102144999A CN 201010107770 CN201010107770A CN102144999A CN 102144999 A CN102144999 A CN 102144999A CN 201010107770 CN201010107770 CN 201010107770 CN 201010107770 A CN201010107770 A CN 201010107770A CN 102144999 A CN102144999 A CN 102144999A
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Abstract
The invention discloses a novel pharmaceutical application of senkyunolide H (represented by formula I). The invention adopts an animal model to study the influence of the senkyunolide H on the cerebral blood flow change in an MCAO (middle cerebral artery occlusion)-caused local cerebral ischemia reperfusion rat model and a KCl (potassium chloride)-induced cortical spreading depression rat model. Pharmacological results prove that senkyunolide H can remarkably increase the cerebral blood flow of a rat after MCAO modeling, and rapidly restore or even exceed the original cerebral blood flow before modeling after filling is performed, and show a certain brain protection effect. In addition, senkyunolide H can resist the cerebral blood flow decrease caused by KCl-induced rat local cerebral vasoconstriction, Therefore, senkyunolide H can be used for preparing a medicine for preventing and curing cerebral apoplexy.
Description
Technical field
The present invention relates to Chemistry for Chinese Traditional Medicine and medical technical field, be specifically related to from Rhizoma Chuanxiong (Ligusticumchuanxiong Hort.), extract the new medical use of the senkyunolide H (senkyunolide H) of preparation.
Background technology
Rhizoma Chuanxiong (Ligusticum chuanxiong Hort.) is a Umbelliferae Ligustrum plant, and its medicinal part is a rhizome.Rhizoma Chuanxiong is China's Chinese medicine, has blood-activating and qi-promoting, the effect of wind-expelling pain-stopping, and Eastern Han Dynasty's Shennong's Herbal is classified it as top grade, is treatment depression and migrainous conventional Chinese medicine.
Phthalide analog compound is a compounds that is present in the Rhizoma Chuanxiong, and being proved to be is having activity aspect cardiovascular, blood and the smooth muscle.Wherein study more butylphthalide and have many activity such as anti-cerebral ischemia, protection cerebral trauma tissue, can be considered to one of material base of Rhizoma Chuanxiong drug effect.
Senkyunolide H (Senkynolide H, its chemical structural formula is seen (I)) separates a kind of phthalide analog compound that obtains in Rhizoma Chuanxiong, have well fat-soluble and water solublity, can enter blood and cerebrospinal fluid rapidly, has the potentiality of certain developing new drug.But at present still less to the report of its pharmacological action, only find that it can alleviate ConA and draw erythrocytic morphotropism damage, reduce its aggregation (time precious traditional Chinese medical science traditional Chinese medicines, 2003,14 (12): 738-739.); Flow in the calcium of inhibition guinea pig myocardium cell and human nerve cell tumor etc. (ClinExp Pharmacology Physion, 1999,26:845-846.).Do not see that as yet it has active report and patent in anti-cerebral ischemia, protection cerebral trauma organizational aspects.
Summary of the invention
Technical problem to be solved by this invention is the novel medical use that proposes senkyunolide H, i.e. application in preparation control apoplexy medicine.
The present invention's extraction separation from Rhizoma Chuanxiong obtains the senkyunolide H (structural formula (I)) of q.s, by pharmacological evaluation, has confirmed that the senkyunolide H of following structural formula (I) expression can be used for preventing and treating apoplexy and convalescence treatment thereof.
The extraction separation of senkyunolide H of the present invention adopts conventional alcohol extraction chromatography, mainly comprises the steps:
(1) pre-treatment step: will be ground into powder behind the Rhizoma Chuanxiong decoction pieces removal impurity to be extracted;
(2) extraction step: with 70% ethanol serves as to extract solvent, makes the volume (liters) that extracts solvent and the ratio of the weight (kilogram) of medical material to be extracted reach 10: 1,90 ℃ of reflux, extract, 2 times, and each 2 hours, merge extractive liquid,, the recovery solvent gets extract A;
(3) chromatographic purification step: extractum separates with normal phase silica gel column chromatography, and is to carry out eluting at 100: 1 with the chloroform-methanol volume ratio, with eluent thin-layer silicon offset plate (GF
254) observe down in uviol lamp 254nm behind the point sample, collect the part that contains senkyunolide H, and decompression and solvent recovery, must be through the extractum of silica gel chromatography purification; Utilize C once more
18Reversed-phase silica gel column chromatography separates, and the 30%-50% methanol-eluted fractions is with eluent thin-layer silicon offset plate (GF
254) observe down in uviol lamp 254nm behind the point sample, collect the part that contains senkyunolide H, and decompression and solvent recovery, promptly get the senkyunolide H of purification.
The present invention adopts animal model; studied that senkyunolide H causes the local cerebral ischemia re-perfusion model to rat mesencephalic arteries blocking-up (MCAO) and potassium chloride (KCL) is induced the influence that the rat brain blood flow changes in the rat layer spreading depression model; pharmacology result confirms that senkyunolide H can significantly improve the cerebral blood flow of rat after the MCAO modeling; and can pour into the rapid recovery in back again and, demonstrate certain cerebral protection above original cerebral blood flow before the modeling.In addition, senkyunolide H can resist by the local cerebrovascular of the inductive rat of KCL and shrink the situation that cerebral blood flow descends that causes, and therefore, senkyunolide H can be used for preparation control apoplexy and convalescence associated treatment medicine thereof.
The specific embodiment
The reagent and the animal of adopting in following examples and the test example are described as follows:
1. reagent
Tlc silica gel (GF254, lot number 080130) is purchased in Qingdao Marine Chemical Co., Ltd.; Methanol (sigma company, chromatographically pure); Senkyunolide H (making purity 98.2% by embodiment 1 method); KCL injection (Chemical Reagent Co., Ltd., Sinopharm Group, lot number 20090928); Butyphthalide capsule (Enbipu Pharmacy Co., Ltd., Shiyao Group., lot number 09060211); Chloral hydrate (Chemical Reagent Co., Ltd., Sinopharm Group, lot number 20060220); Normal saline (the rich Pharmaceutical of Shanghai Hua Yuanchang Group Co.,Ltd, lot number 08032501); Laser Doppler flowmetry (PeriFlux System 5000, PERMED, USA); The Rhizoma Chuanxiong medical material is awarded the dry rhizome that is accredited as samphire Rhizoma Chuanxiong (Ligusticum chuanxiong Hort.) through the Shanghai Univ. of Traditional Chinese Medicine's Zhao Zhi of crude drug teaching and research room the Confucian or feudal ethical codes, available from Cambridge, Shanghai decoction pieces company (lot number 071215, Sichuan, the place of production).
2. animal
100 of SD rats, male, body weight (260 ± 20) g is provided by Shanghai Univ. of Traditional Chinese Medicine's Experimental Animal Center, the animal quality certification number: SCXK (Shanghai) 2008-0016S.
Embodiment 1. alcohol extracting method chromatographs prepare senkyunolide H
Rhizoma Chuanxiong decoction pieces 1kg is ground into powder behind the removal impurity, 70% ethanol 10L reflux, extract, 2 times, and each 2 hours, merge extractive liquid, reclaimed solvent and gets the about 100g of extractum A.Extractum is separated (silica gel is 100-200 order or 200-300 order column chromatography silica gel, and extractum sample and silica gel weight ratio are 1: 30) with silica gel column chromatography, and be to carry out eluting at 20: 1, with eluent thin-layer silicon offset plate (GF with the chloroform-methanol volume ratio
254) observe down in uviol lamp 254nm behind the point sample, collect the part that contains senkyunolide H, and decompression and solvent recovery; The anti-phase C of gained extractum
18Silica gel column chromatography separates (extractum sample and C
18The reverse phase silica gel weight ratio is=1: 30), and to discard eluent behind the methanol-water volume ratio 30% eluting 5BV, reuse methanol-water volume ratio is 50% eluting 5BV, with eluent thin-layer silicon offset plate (GF
254) observe down in uviol lamp 254nm behind the point sample, collect the part that contains senkyunolide H, and decompression and solvent recovery, promptly get the about 0.3g of senkyunolide H of purification.
The preparation of embodiment 2. senkyunolide H tablets
Every consumption of composition
Senkyunolide H 100mg
Lactose 37.45mg
Microcrystalline Cellulose 17.5mg
Starch 21.0mg
Magnesium stearate 1.05mg
By recipe quantity senkyunolide H (making by embodiment 1 method) is added mixing behind lactose, microcrystalline Cellulose, the starch, make granule, add magnesium stearate, mixing, tabletting promptly gets (every contains senkyunolide H 0.1g).The oral consumption 1-4 sheet of adult's recommendation/time, every day 2-3 time.
The capsular preparation of embodiment 3. senkyunolide H
Every consumption of composition
Senkyunolide H 100mg
Microcrystalline Cellulose 37.45mg
Micropowder silica gel 10.5mg
Stearic acid 17.5mg
Lactose 10.5mg
By recipe quantity senkyunolide H (making by embodiment 1 method) is added mixing behind lactose, microcrystalline Cellulose, micropowder silica gel, the stearic acid, make granule after, be filled into hard capsule case No. 0, polishing promptly makes (every capsules contains senkyunolide H 0.1g).The oral consumption 1-4 grain of adult's recommendation/time, every day 2-3 time.
Routine pharmacological activity test and result with senkyunolide H further specifies the present invention below by test.
The influence that test example 1. senkyunolide H change rat local cerebral ischemia re-perfusion model midbrain blood flow
50 of Sprague-Dawley (SD) rats, male, body weight (260 ± 20) g, be divided into 5 groups at random: sham operated rats, model group, the positive drug group (butyphthalide, 72mg/kg), senkyunolide H (senkyunolide H) high dose group (72mg/kg), senkyunolide H low dose group (36mg/kg) (senkyunolide H makes by embodiment 1 method).Fasting 12h before the experiment freely drinks water.Modeling method: adopt Longa line bolt to send out and make the local cerebral ischemia re-perfusion model, cerebral ischemia 1h pours into 24h again.The every 100g lumbar injection of rat 0.35mL10% chloral hydrate anesthesia is made the epigastrium otch, reserves the duodenal administration window.It is fixing to lie on the back, conventional epidermis sterilization, the neck median incision, from separating exposure right carotid (CCA), external carotid artery (ECA) to the deep between muscle group, careful separation is avoided damaging vagus nerve, internal carotid artery (ICA), is upwards continued to separate arteria pterygopalatina (PPA) along ICA.Ligation ECA distal end, in ECA proximal part hanging wire, the temporary transient folder of arteriole folder closes CCA distal end and PPA, in the middle of the ligation of ECA two places, cut an osculum, with the line bolt for preparing along otch slow axis of thrust bolt of continuation after the ECA proximal part is advanced into the CCA folder place of closing and turns to the bottom right to be advanced into ICA, the power that is hampered stops, the about 16～18mm of insertion depth (deciding according to the weight of animals).Tighten up ECA proximal part hanging wire static line bolt, removing two place arteriole folder can inaccessible brain mesencephalic arteries blood flow, and ischemia reaches the careful about 1cm of outer pulling plug line behind the 1h, i.e. formation is poured into again.Sham operated rats line bolt only inserts 10mm, and all the other steps are with each group.1.5mm behind the rat bregma, the other drill diameter 1mm of the 5mm place aperture of opening in center line right side is inserted fibre-optical probe to brain cortex surface, before the continuous detecting MCAO behind basic value (pre), the duodenal administration, among the MCAO1h and pour into the interior cerebral blood flow value of (rep) 30min again.Every 5-10min writes down one group of data.During analysis, be basic blood flow value, calculate in the ischemia, after the administration and irritate the different time-histories local cerebral blood flow numerical value percentage ratios in back again with the cerebral blood flow value before the ischemia.
The influence that table 1. senkyunolide H changes rat local cerebral ischemia re-perfusion model midbrain blood flow
Annotate: compare with model group,
*P＜0.05,
*P＜0.01
Test example 2. senkyunolide H induce the influence of rat layer spreading depression model to KCL
50 of SD rats, male, body weight (260 ± 20) g, be divided into 5 groups at random: sham operated rats, model group, the positive drug group (butyphthalide, 72mg/kg), senkyunolide H (senkyunolide H) high dose group (72mg/kg), senkyunolide H low dose group (36mg/kg) (senkyunolide H makes by embodiment 1 method).Fasting 12h before the experiment freely drinks water.Modeling method: the every 100g lumbar injection of rat 0.35mL10% chloral hydrate anesthesia, make the epigastrium otch, reserve the duodenal administration window.1.5mm behind the rat bregma, the other drill diameter 1mm of the 5mm place aperture of opening in center line right side is inserted fibre-optical probe to brain cortex surface, behind the stable recording cerebral blood flow value 5min, in drill hole injection 1moL/LKCL5 μ L, duodenal administration immediately.The sham operated rats survey cerebral blood flow of only holing, normal saline is given in model group boring back.The interior cerebral blood flow value of 30min behind (basic value), the duodenal administration before the fibre-optical probe continuous detecting KCL injection.Every 5min writes down one group of data.During analysis, be basic blood flow value with the cerebral blood flow value before the KCL injection, different time-histories local cerebral blood flow numerical value percentage ratios behind the calculating injection KCL, after the administration.
Table 2. senkyunolide H induces the influence of rat layer spreading depression model to KCL
Annotate: compare with model group,
*P＜0.05,
*P＜0.01
Above The pharmacological results shows, senkyunolide H can significantly improve the cerebral blood flow of rat after the MCAO modeling, and can be before perfusion back be again recovered rapidly and is surpassed modeling original cerebral blood flow, demonstrate certain cerebral protection.In addition, senkyunolide H can resist by the local cerebrovascular of the inductive rat of KCL and shrink the situation that cerebral blood flow descends that causes.
From the research data of present accumulation, senkyunolide H tentatively possesses as effectively preparing control apoplexy and convalescence associated treatment thereof the primary condition with medicine.Therefore, senkyunolide H can be used for preparation control apoplexy and convalescence associated treatment medicine thereof among the present invention.
Claims (1)
1. the application of the senkyunolide H of following structural formula (I) expression in preparation control apoplexy medicine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115837040A (en) * | 2022-12-06 | 2023-03-24 | 四川省中医药科学院 | Application of ligusticum wallichii extract in preparation of medicine for preventing and treating cognitive disorder |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20090078777A (en) * | 2006-08-11 | 2009-07-20 | 디에스엠 아이피 어셋츠 비.브이. | Ligustilide derivatives for the treatment of disorders of the central nervous system |
| CN101015552A (en) * | 2006-12-29 | 2007-08-15 | 天津大学 | Ligustilide extract and its preparing process and application |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115837040A (en) * | 2022-12-06 | 2023-03-24 | 四川省中医药科学院 | Application of ligusticum wallichii extract in preparation of medicine for preventing and treating cognitive disorder |
| CN115837040B (en) * | 2022-12-06 | 2024-03-08 | 四川省中医药科学院 | Application of ligusticum chuanxiong hort extract in preparation of medicine for preventing and treating cognitive dysfunction |
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