CN105726537A - Application of domperidone in preparation of therapeutics for cerebral ischemia-reperfusion injury - Google Patents
Application of domperidone in preparation of therapeutics for cerebral ischemia-reperfusion injury Download PDFInfo
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- CN105726537A CN105726537A CN201610148324.9A CN201610148324A CN105726537A CN 105726537 A CN105726537 A CN 105726537A CN 201610148324 A CN201610148324 A CN 201610148324A CN 105726537 A CN105726537 A CN 105726537A
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- reperfusion injury
- cerebral ischemia
- domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Abstract
The invention provides application of domperidone in the preparation of therapeutics for cerebral ischemia-reperfusion injury.It is discovered herein that domperidone has excellent protection for cerebral ischemia-reperfusion injury, specifically, domperidone can improve neurofunction deficit due to cerebral ischemia-reperfusion injury, reduce cerebral water content, reduce infarcted focal size, improve infarcted focus activity and reduce malondialdehyde level; expression of inflammatory factors such as IL-1 and IL-6 is reduced, thus reducing excessive inflammatory response of ischemic cerebrum tissues and providing post-ischemic neural protection.The clear therapeutic effect, effective dosage and administration mode of domperidone in treating cerebral ischemia-reperfusion injury are determined through mass test data, and a new way to treat cerebral ischemia-reperfusion injury is provided.
Description
Technical field
The present invention relates to the new application of compound domperidone, be specifically related to domperidone for preparing cerebral ischemia re-pouring
The application of injury in treating medicine
Background technology
Cerebrovascular is one of three big diseases causing human death, and its high mortality, high disability rate give society and family
Bring white elephant.Brain is the organ that human body is most sensitive to anoxia, and brain tissue ischemia (ischemia) will cause office
Portion's cerebral tissue and the infringement of function thereof, its extent of damage is the most relevant with Ischemia Time length and remaining blood flow, and short-term is the completeest
Full property ischemia only causes reversibility to damage, and ischemia or severe ischemic can cause infarction the most completely.
After brain tissue ischemia, microglia, astrocyte are activated, and produce substantial amounts of cytokine and chemistry
Chemotactic factor.Cytokine makes cerebrovascular endothelial cell expression of adhesion molecule raise, the leukocyte in circulation at adhesion molecule and
Under the effect of chemotactic factor, stick and migrate to the brain essence of damage, discharge substantial amounts of il-1 together with glial cell
(IL-1), the cytokine such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), thus strengthen leukocyte infiltration, with
Time the substantial increase of the inflammatory mediator such as arachidonic acid metabolite, increase the weight of local damage, ultimately result in neuronal apoptosis, bad
Extremely.
Cerebral ischemia re-pouring can cause brain function to be badly damaged.During cerebral ischemia, brain cell bio electricity changes, and disease occurs
Rationality slow wave, Reperfu-sion after ischemia certain time, slow wave continues and increases the weight of.In temporal lobe tissue, neurotransmitter acidic amino acid metabolism is sent out
Raw significant change, i.e. excitatory amino acid (glutamic acid and aspartic acid) are gradually lowered with ischemia-reperfusion time lengthening,
Inhibitory aminoacid (alanine, γ-aminobutyric acid, taurine and glycine) is the most significantly raised at ischemia-reperfusion.Ischemia
The reperfusion injury time is the longest, and excitatory transmitter content is the lowest, and brain tissue ultrastructure changes the most obvious: mitochondrial swelling, has
Calcium deposition, and the fracture of visible mitochondrial crista, nuclear chromatin coagulation, endoplasmic reticulum height swelling, structure is substantially destroyed, astrocytes
Swelling, Nissl body integrity violations, glial cell, vascular endothelial cell swelling, peripheral clearance increases and has pale red edema
Loosening in liquid, white matter fiber gap, Ink vessel transfusing, by microthrombus, myelin layering degeneration, presents irreversible damage.
In prior art, related methods for the treatment of mainly includes two aspects, and one is to recover brain to fill again, improves cerebral blood supply (molten
Bolt)；Two is to block Cascade of Injury, prevents neuronal damage (brain protection).For the complexity of its pathomechanism, except super
Early thrombolysis has outside definite curative effect, not yet has a kind of neuroprotective proving for evidence-based medicine EBM and having curative effect certainly.Domperidone,
The chloro-1-of 5-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazole-1-base) propyl group] piperidin-4-yl]-1,3-dihydro-2H-
2-ketone benzimidaozole, in prior art, domperidone is as periphery dopamine receptor antagonist, is mainly used in promoting digestive tract power reinforcing medicine
Thing, directly acts on gastrointestinal wall after being administered orally, can increase lower esophageal sphincter tension force, prevents stomach-esophageal regurgitation, strengthens stomach compacted
Dynamic, promote two emptyings.Prior art not finding, domperidone is used for treating the application of cerebral ischemia reperfusion injury.
Summary of the invention
The invention provides domperidone application in terms of preparation treatment cerebral ischemia reperfusion injury medicine, thus provide
A kind of new medical usage of domperidone, also provides a kind of new way of cerebral ischemia reperfusion injury treatment simultaneously.
Another technical problem that the present invention solves is an up the therapeutic effect of cerebral ischemia reperfusion injury.
For realizing above technical purpose, the present invention by the following technical solutions:
Domperidone is for preparing the application of cerebral ischemia reperfusion injury medicine.
Preferably, described cerebral ischemia reperfusion injury is because of the nervous function damage caused by cerebral ischemia re-pouring.
Preferably, described cerebral ischemia reperfusion injury is because of the brain tissue inflammation caused by cerebral ischemia re-pouring；Basis at this
It is upper it is further preferred that described brain tissue inflammation is the brain tissue inflammation as effect with IL-1 β or IL-6 overexpression.
Preferably, described cerebral ischemia reperfusion injury is the cerebral ischemia reperfusion injury of cerebral infarction disease.
Preferably, described medicine is oral agents.
Preferably, described medicine is injection.
Heretofore described domperidone is the compound that chemical constitution shown in accompanying drawing 5 is limited.
It is a discovery of the invention that domperidone has preferable neuroprotective to focal cerebral ischemia-reperfusion in mice, can change
Neurological deficit after kind cerebral ischemia reperfusion injury, alleviates brain water content, reduces infarct cerebral volume, increases superoxide dismutase
Change enzyme activity, reduce the content of malonaldehyde；Reduce the expression of the Pro-inflammatory Cytokines such as IL-1, IL-6 simultaneously, thus alleviate cerebral ischemia-reperfusion
The excessive inflammatory response of tissue, it is achieved the neuroprotective after ischemia.
The present invention determines domperidone for treating the effective of cerebral ischemia re-pouring damage by a large amount of animal experimental datas
Dosage is 45-55mg/Kg body weight/day, and the present invention can also can be administered by injection system by oral administration.
Accompanying drawing explanation
Fig. 1 is the neurologic impairment figure caused after domperidone improves middle cerebral artery ischemia.
Fig. 2 is that domperidone alleviates the aqueous spirogram of Mice brain tissues.
Fig. 3 is the Infarction volume figure after domperidone alleviates focal brain ischemia-reperfusion injury.
Fig. 4 is that domperidone reduces the expression effect figure of inflammatory factor after brain tissue ischemia Reperfu-sion.
Fig. 5 is the structural formula of domperidone of the present invention.
Detailed description of the invention
1 experimental technique
The foundation of 1.1MCAO mouse model
(1) laboratory animal and source
Male wild-type C57/BL6 pathogen-free domestic (SPF level) mice 72,6-8 week old, body weight 25-30g, raising of mice
Foster environment is room temperature 20-25 DEG C, relative humidity 40%-60%.
(2) experiment packet
For research domperidone medicine effect in mice MCAO animal model, mice is randomly divided into three groups, often organizes 24
Only, respectively sham operated rats；Ischemia-reperfusion injury model group (model group)；Domperidone treatment group (treatment group).Treatment group and system
Standby MCAO model gives domperidone 50mg/Kg/ days gavages in first 7 days.Sham operated rats and model group prepare first 7 days in MCAO model
Give and the normal saline gavage for the treatment of group same volume.Model group and treatment group mice use Longa line brush to set up MCAO
Model, ischemia 1h, Reperfu-sion 24h.
(3) experimental procedure
A. mouse weights, 10% chloral hydrate (3ml/Kg) intraperitoneal injection of anesthesia, its dorsal position is fixed on dissection operation
On platform, with left side middle cerebral artery for operation side, cervical region preserved skin, iodophor disinfection；
B. median incision before row cervical region, cuts off skin, separates subcutaneous tissue, exposes bubbling gland and pushes it against both sides, blunt
Property chorista, expose common carotid sheath；
C. blunt separation common carotid artery (common carotid artery, CCA), internal carotid artery (intemal
Carotid artery, ICA), external carotid artery (external carotid artery, ECA) and the Main Branches tremulous pulse of ECA
Occipital artery, superior thyroid artery etc., protection peripheral nerve such as vagus nerve is injury-free；
The most first ligature the Main Branches tremulous pulse of ECA, ligature CCA proximal part, put a standby silk thread at distal end and slightly ligature,
Give over to fixing line bolt use, put a standby silk thread at ICA proximal part, give over to hemostasis and use；
E. on CCA, cut a v-notch between two ligatures, the line bolt got ready is inserted in CCA, slightly tightens up telecentricity
End ligature, the crotch that line bolt is crossed ECA and ICA enters ICA tube chamber, slowly sends into intracranial, when running into light resistance
(mean depth of insertion is dynamic inside and outside neck to the initial part of arrival middle cerebral artery (middle cerebral artery, MCA)
Arteries and veins crotch 9-10mm), tighten up and ligature the ligature on CCA；
F. confirmation wound is without oozing of blood, layer-by-layer suture muscle and skin, iodophor disinfection operative incision, and line bolt ends exposed is at skin
Outside skin, and by its labelling；
G. after ischemia 1h, line bolt is exited about 5mm, but line bolt head is still retained in the ECA broken ends of fractured bone, so that mice realizes again
Perfusion, cuts off the redundance of line bolt；
H. Postoperative insulation and the nursing of otch, operated cohort is single cage raising after reviving, and keeps mouse cage dry cleansing, supplies
Answer liquid, close observation.
I. sham operated rats model is prepared ibid, but inserts line bolt the most about 5mm, i.e. line bolt be not inserted into ICA cranium through ECA sidewall
Inner segment.
(4) inclusion criteria of MCAO model
With reference to the method for Zea Longa, after mice surgery anesthesia be clear-headed, carry out 5 points of systems mark:
0 point: impassivity function damage symptom；
1 point: when carrying tail, thromboembolism tremulous pulse offside forelimb can not stretch；
2 points: rotate to thromboembolism tremulous pulse offside during walking；
3 points: topple over to thromboembolism tremulous pulse offside during walking；
4 points: can not spontaneous walk, loss of consciousness.
Scoring enters group the 1-3 person of dividing.
(5) exclusion standard of MCAO model
A. according to Zea Longa point system, Neuroscore is less than 1 point of person；
Concurrent subarachnoid hemorrhage person is found when b. taking brain；
The c.TTC dyeing person that has no ischemic focus；
D. died in ischemia-reperfusion 24h.
Because above-mentioned factor causes each test group of animals number deficiency person, polishing number of animals again modeling at any time.
1.2 neurological deficits score
After mice surgery anesthesia is clear-headed, use neurological deficits score (the modified neurological of improvement
Severity scores, mNSS) motion, sensation, equilibrium function and the reflection of mice are evaluated, scoring scope is 0-18
Point, score value is the highest, and its nervous lesion is the most serious, and wherein, 13-18 is divided into major injury, 7-12 to be divided into moderate lesion, 1-6 to be divided into
Minor injury, 0 is divided into not damaged.
Table 1: the neurological deficits score (mNSS) of improvement
The evaluation of 1.3 mouse brain Infarction volume
Cerebral infarction volume is evaluated by application TTC dyeing.
After MCAO mice ischemia-reperfusion 24h, fix with dorsal position after 10% chloral hydrate excess anesthesia, quickly open breast sudden and violent
No. 16 syringe needles are inserted to aortic root by apex by dew heart, and blood vessel clamp closes ventral aorta, cuts off right auricle simultaneously and puts
Blood.Through 4 DEG C of normal saline about 100ml of heart quick filling, till effluent becomes clearly.After perfusion, broken end takes brain immediately,
Remove olfactory bulb, cerebellum and low brain stem, take out after freezing 20min in-20 DEG C of refrigerators, from forebrain antinion, cut out 5 the most continuously
The Coronal brain section of sheet thickness about 2mm.Being put into by brain sheet in the 1%TTC solution prepared in advance, 37 DEG C of lucifuges are hatched about
When 30min, 15min, brain sheet turn-over is once so that it is with TTC uniform contact.Then brain sheet is placed in freshly prepared 4% poly first
Fixing 24h in aldehyde solution, observe and take pictures, normal cerebral tissue is cerise, does not dyes and in pale asphyxia in necrotic area.
Analyze: application Image J image (Media Cybernetics, Inc) processes computed in software Infarction volume and accounts for homonymy
The percentage ratio of brain volume.Consider the impact of cerebral edema, the Infarction volume computing formula after employing correction: the measurement infarction face of correction
Infarct size × { 1 one [(a pair side hemisphere area of homonymy hemisphere the area)/homonymy hemisphere area] } of long-pending=measurement.
1.4 Mice brain tissues moisture determinations
Use dry and wet weight method, take cerebral tissue thick for pathological changes side about 2mm after removing antinion and measure for brain water content.
(1) being put into by cerebral tissue in the tinfoil of weigh in advance (A), weigh (B) immediately, and B-A i.e. obtains weight in wet base；
(2) wrapping up cerebral tissue with tinfoil, put into taking-up after 95 DEG C of baking boxs dry 24h and return to room temperature, weigh (C), C-A
Obtain dry weight, repeatedly weigh to constant weight；
(3) substitution formula calculating brain water content: (cerebral tissue weight in wet base-cerebral tissue dry weight)/weight in wet base × 100%, i.e. (B-
C)/(B-A) × 100%.
The content of inflammatory factor in 1.5 enzyme linked immunosorbent assay Mice brain tissues supernatants
(1) shift to an earlier date 20min from refrigerator, take out test kit, with balance to room temperature；
(2) Wash buffer diluent: with distilled water with 1: 10 dilution, 50ml wash buffer adds 450ml distilled water
To 500ml；
(3) Assay buffer diluent: with distilled water with 1: 20 dilution, 5ml assay buffer adds 95ml distilled water
To 100ml；
(4) Sample Dilution Buffer diluent: 2ml 10%BSA adds Sample Dilution Buffer extremely
20ml；
(5) preparation (Avidin-HRP) of HRP junctional complex: with the Assay buffer liquid of 1 times with 1: 1000 dilution, 11 μ l
Liquid at the bottom of HRP junctional complex joins in 11ml Assay buffer.
(6) preparation of Antigen Standard Cocktail: 12 kinds of antigen standard are respectively drawn 10 μ l and puts into 880
In the Sample Dilution Buffer of μ l dilution, it is configured to the Antigen Standard Cocktail concentrated, then with dilute
The Sample Dilution Buffer released is configured to Final Antigen Standard Cocktail. by 1: 4
(7) Dection Antibodies diluent: add 855 μ l respectively in 12 kinds of Detection Antibodies
Assay Buffer mixes.
(8) from balancing to the sealing bag of room temperature the required lath of taking-up test；
(9) add 50 μ l Assay Buffer to each hole with multichannel pipettor and wash plate:
(10) sample-adding: respectively specimen and 12 kinds of standard substance are added in respective aperture (50ul/ hole), seal instead with shrouding gummed paper
Ying Kong, incubated at room 2h；
(11) plate is washed 3 times:
(12) the Dection Antibody Solution of 100 μ l dilutions, incubated at room 1h are added；
(13) plate is washed 4 times；
(14) 100 μ l Avidin-HRP, incubated at room 30min are added；
(15) plate is washed 4 times；
(16) adding 100 μ l Development Solution, room temperature lucifuge hatches 15min；
(17) add 100 μ l Stop Solution, at microplate reader 450nm, read OD value.
2 experimental results
Result shows: sham operated rats mNSS is 0, points out impassivity functional impairment；Model group mNSS is 11.45 scholars 1.57,
Treatment group mNSS is 8.55 scholars 0.09, model group and treatment group apparently higher than sham operated rats, makes after prompting middle cerebral artery ischemia
Become obvious neurologic impairment.Compared with model group, the scoring for the treatment of group mNSS substantially reduces, as shown in table 2, Fig. 1.Prompting
Domperidone can improve the neurologic impairment caused by cerebral ischemia reperfusion injury, has neuroprotective.
The brain water content result recorded by dry and wet weight method shows: compared with sham operated rats, model group Mice brain tissues
Water content is significantly raised, and treatment group Mice brain tissues water content is obviously reduced, as shown in table 2, Fig. 2.
Ischemical reperfusion injury makes mouse brain bigger infarcted region occur, and mean infarct volume is 34.59%, before ischemia
Within 7 days, giving domperidone can make Infarction volume reduce, and Infarction volume is reduced significantly compared with model group, as shown in table 2, Fig. 3.Brain
The change prompting domperidone of Infarction volume can alleviate the Infarction volume after focal brain ischemia-reperfusion injury, thus produces
Cerebral protection.
Table 2: the scoring of mouse Nerve functional impairment and cerebral infarction volume compare
Compared with model group,aP ＜ 0.05
ELISA multiple-factor testing result shows: after brain tissue ischemia Reperfu-sion, the inflammatory Cytokines Expression such as IL-1 β, IL-6 is bright
Aobvious rising, and the expression of these proinflammatory factors can be made substantially to reduce, as shown in Figure 4 after domperidone treatment.
Data above shows from multiple angles, and domperidone has definite therapeutic effect to cerebral ischemia reperfusion injury.
Above embodiments of the invention are described in detail, but described content have been only presently preferred embodiments of the present invention,
Not in order to limit the present invention.All any amendment, equivalent and improvement etc. made in the application range of the present invention, all should
Within being included in protection scope of the present invention.
Claims (7)
1. domperidone is for preparing the application of cerebral ischemia reperfusion injury medicine.
Application the most according to claim 1, it is characterised in that described cerebral ischemia reperfusion injury is because of cerebral ischemia re-pouring
Caused nervous function damage.
Application the most according to claim 1, it is characterised in that described cerebral ischemia reperfusion injury is because of cerebral ischemia re-pouring
Caused brain tissue inflammation.
Application the most according to claim 3, it is characterised in that described brain tissue inflammation is with IL-1 β or IL-6 overexpression
Brain tissue inflammation for effect.
Application the most according to claim 1, it is characterised in that described cerebral ischemia reperfusion injury is the brain of cerebral infarction disease
Ischemical reperfusion injury.
Application the most according to claim 1, it is characterised in that described medicine is oral agents.
Application the most according to claim 1, it is characterised in that described medicine is injection.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610148324.9A CN105726537A (en) | 2016-03-11 | 2016-03-11 | Application of domperidone in preparation of therapeutics for cerebral ischemia-reperfusion injury |
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| CN201610148324.9A CN105726537A (en) | 2016-03-11 | 2016-03-11 | Application of domperidone in preparation of therapeutics for cerebral ischemia-reperfusion injury |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111084765A (en) * | 2019-12-11 | 2020-05-01 | 中国药科大学 | Application of cannabidiol hydrate in preparation of medicine for preventing and/or treating brain injury and medicine composition of cannabidiol hydrate |
| CN115501223A (en) * | 2022-10-08 | 2022-12-23 | 青岛大学 | Application of farrerol in preparation of medicine for resisting cerebral ischemia reperfusion injury |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405408A (en) * | 2013-06-27 | 2013-11-27 | 郝峻巍 | Application of chrysin in preparation of medicines for treating cerebral arterial thrombosis |
-
2016
- 2016-03-11 CN CN201610148324.9A patent/CN105726537A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405408A (en) * | 2013-06-27 | 2013-11-27 | 郝峻巍 | Application of chrysin in preparation of medicines for treating cerebral arterial thrombosis |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111084765A (en) * | 2019-12-11 | 2020-05-01 | 中国药科大学 | Application of cannabidiol hydrate in preparation of medicine for preventing and/or treating brain injury and medicine composition of cannabidiol hydrate |
| CN111084765B (en) * | 2019-12-11 | 2022-03-08 | 中国药科大学 | Application of cannabidiol hydrate in preparation of medicine for preventing and/or treating brain injury and medicine composition of cannabidiol hydrate |
| CN115501223A (en) * | 2022-10-08 | 2022-12-23 | 青岛大学 | Application of farrerol in preparation of medicine for resisting cerebral ischemia reperfusion injury |
| CN115501223B (en) * | 2022-10-08 | 2024-01-16 | 青岛大学 | Application of azalea essence in preparing medicine for resisting cerebral ischemia reperfusion injury |
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Application publication date: 20160706 |