CN108888612A - Application of borneol as active ingredient of medicine for relieving opening of blood brain barrier caused by focal cerebral ischemia induced by ultrasonic targeted microbubble disruption technology - Google Patents
Application of borneol as active ingredient of medicine for relieving opening of blood brain barrier caused by focal cerebral ischemia induced by ultrasonic targeted microbubble disruption technology Download PDFInfo
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- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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Abstract
The invention relates to a new application of compound borneol in the field of pharmacy, and discloses an application of borneol as an active ingredient in a medicine for relieving the opening of a blood brain barrier of focal cerebral ischemia induced by an ultrasonic targeted microbubble disruption technology (UTMD). Borneol can relieve further opening of UTMD to cerebral ischemia blood brain barrier, thereby providing a safer strategy for UTMD as an auxiliary neuroprotective treatment after stroke.
Description
Technical field
It is specifically to be related to borneol to surpass as mitigation that the present invention relates to compound borneols in the new application of pharmaceutical field
Sound targeted microbubble bursting technologies induce the application of active constituent in the drug of focal cerebral ischemia Blood Brain Barrier (BBB) opening.
Background technique
The main reason for stroke is the second largest common cause for causing death in world wide and acquired deformity.By several
To the research of Ischemic Stroke neuroprotective agent over 10 years, the achievements conversion that is also not yet succeeded so far.This is because blood brain
Barrier is a kind of height permselectivity barrier, it effectively separates blood circulation with central nervous system, and is remaining big
Key effect is played in brain homeostasis.Blood-brain barrier opens during cerebral ischemia re-pouring, this theoretically permits
Permitted neuroprotective agent and enters impaired brain tissue.However, even if the open to the outside world of the blood-brain barrier induced by cerebral ischemia, targeting
Delivering neuroprotective agent may still be obstructed.Therefore, the Neuroprotective Therapy in Treating Acute of Ischemic Stroke there is an urgent need to can induce safety and
The novel therapeutic strategy of further Blood Brain Barrier (BBB) opening.
More and more evidences from zooscopy show ultrasound targeted microbubble bursting technologies (UTMD) by instantaneously beating
Blood-brain barrier is opened, is delivered to specific brain area so as to Noninvasive and selectively by therapeutic agent.Also studies have reported that
UTMD has direct protective effect to cerebral arterial thrombosis, this technology is increasingly recognized to be hopeful as Ischemic Stroke
One of adjuvant treatment.Not excessive researcher is busy with probing into how UTMD effectively assists neuroprotective agent to treat nervous centralis
While systemic disease, also studies have reported that the machinery of UTMD and cavitation is claimed to will lead to normal brain tissue bleeding.Meanwhile
The preliminary experiment of inventor shows that the parameter aggravation of a kind of open normal mouse blood-brain barrier safety of UTMD and rather moderate lacks
Hemorrhagic stroke blood-brain barrier of mice opens and leads to the micro bleeding of brain.These are found to be UTMD as Post stroke auxiliary therapy
Clinical application propose an important safety issue.
Borneol is that China's traditional Chinese medicine " is had one's ideas straightened out " the representative drug of medicine, is the fat-soluble Monoterpenes of small molecule.Ice
The fat-soluble active ingredient of piece becomes good penetration enhancer, and drug can also be promoted to enter intracerebral through blood-brain barrier.
Ancient Chinese medicine doctor think borneol can priming uplink, rise " assistant ", " making " function meaning be exactly this effect.Modern study also confirms ice
Piece is remarkably improved the blood concentration and bioavilability of drug, and has certain protective effect to ischemic rat brain.
Summary of the invention
The purpose of the present invention is to overcome the deficiencies of the prior art, provides borneol as ultrasound targeted microbubble is mitigated and ruptures
The application of active constituent in the drug of technological guide focal cerebral ischemia Blood Brain Barrier (BBB) opening.
The structural formula of the borneol is shown below：
Wherein, the effective dose of borneol is 200mg/Kg weight.
Borneol of the present invention mitigates as preparation in the drug of UTMD induction focal cerebral ischemia Blood Brain Barrier (BBB) opening
The purposes of active constituent belongs to first public.Since UTMD acts on focal cerebral ischemia blood-brain barrier, induction of blood-brain barrier
Further opening, increase the gap of brain micro blood vessel endothelium, increase the leakage of blood-brain barrier, to cause red thin outside blood vessel
Born of the same parents' leakage, brain water content increase.And pathologic caused by the open to the outside world for the blood-brain barrier that borneol is induced and cerebral apoplexy is opened
It is placed with the difference of matter, opening is that physiological is open, can't cause the pathologic lesion of brain tissue, opposite borneol is to brain group
Also certain protective effect is knitted, for example it can play anti-inflammatory, improvement energetic supersession and the protection to cerebral ischemia/reperfusion injury
Effect.So we study joint borneol and UTMD, discovery borneol can reduce UTMD to the further of cerebral ischemia blood-brain barrier
It is open, to provide safer strategy as the complementary Neuroprotective Therapy in Treating Acute of Post stroke for UTMD, have reality outstanding
Matter feature has significant progress.
Detailed description of the invention
Fig. 1 is each group mouse Evans blue dyestuff leakage scenarios.(a) model group；(b) model+borneol group；(c) model+
UTMD group；(d) model+borneol+UTMD group.(A) leakage of each group mouse brain surface Evans blue；(B) each group right side of mice brain
Tissue Evans Blue leakage quantifies histogram；(C) each group mouse Cerebral cortex leaks Evans blue fluorescence detection；(D) each group mouse
The statistical analysis of Cerebral cortex leakage Evans blue fluorescence intensity.
Fig. 2 is the transmission electron microscope photo of each group mouse Cerebral cortex capillary.(A1) model group；(B1) model+borneol group；
(C1) model+UTMD group；(D1) model+borneol+UTMD group.Micrograph 2 is the enlarged drawing of 1 part of micrograph.EC：Endothelium is thin
Born of the same parents；TJ：Close connection；R：Red blood cell；CA：Alveole.
Fig. 3 A is each group mouse brain cortex tissue morphology.(a) model group；(b) model+borneol group；(c) model+UTMD
Group；(d) model+borneol+UTMD group.
Fig. 3 B is the statistical analysis of each group mouse brain cortical hemorrhage size.
Fig. 4 is the quantitative histogram of each group mouse infarct side brain water content.
Specific embodiment
It draws 0.5ml Tween 80 (Tween80), is diluted in the sterile 0.01M PBS solution of 9ml, then constant volume arrives
5% tween solution is made in 10ml.5% tween solution made from 9ml is taken, 200mg borneol powder is weighed and is dissolved in the 5% of 9ml and spit
Warm solution, then constant volume are made into the mother liquor of 20mg/ml to 10ml, and 4 DEG C of refrigerators save.
Used borneol is dextrorotation borneol, is purchased from Haozhou city benevolence person pharmacy placed in the middle, structural formula is shown below：
Pharmacological evaluation
Its pharmaceutical activity is further illustrated below by way of pharmacological evaluation and result.Experiment side used in following experiments
Method is routine experiment method unless otherwise specified.Material used in following experiments, reagent etc. unless otherwise specified,
It can obtain from commercial channels.
The borneol solution for being 20mg/ml according to the solubility that following methods produce sufficient amount：
It draws 0.5ml Tween 80 (Tween80), is diluted in the sterile 0.01M PBS solution of 9ml, then constant volume arrives
5% tween solution is made in 10ml.5% tween solution made from 9ml is taken, 200mg borneol powder is weighed and is dissolved in the 5% of 9ml and spit
Warm solution, then constant volume are made into the mother liquor of 20mg/ml to 10ml, and 4 DEG C of refrigerators save.Used borneol is dextrorotation borneol, knot
Structure formula is shown below：
Used mouse：25-30g, male, healthy cleaning grade ICR mouse, it is limited to be purchased from Shanghai Jie Sijie experimental animal
Company.ICR mouse rearing conditions：20-24 DEG C of environment temperature, 12 hours/12 hours light and shade alternatings.
Experimental data is indicated with mean ± standard deviation, is compared between multiple groups using ANOVA, * p<0.05 is considered having statistics
Learn meaning.
70 bull ICR mouse are randomly divided into 4 groups：
(1) model group (n=16)：5% tween solution of 0.2ml is given, one time a day, continuous gavage 3 days, last stomach-filling
Row cerebral ischemia re-pouring modeling after 30min.
(2) model+borneol group (n=18)：Borneol solution is given according to the dosage of 200mg/Kg weight, one time a day, continuously
Row cerebral ischemia re-pouring modeling after stomach-filling 3 days, last stomach-filling 30 minutes.
(3) model+UTMD group (n=18)：Through cranium ultrasound wave irradiation after Cerebral Ischemia/Reperfusion 24 hours, at the same it is quiet by tail
Arteries and veins injects SonoVue.
(4) model+borneol+UTMD group (n=18)：Borneol solution is given according to the dosage of 200mg/Kg weight, daily 1
Secondary, row cerebral ischemia re-pouring modeling after continuous gavage 3 days, last stomach-filling 30 minutes passes through after Cerebral Ischemia/Reperfusion 24 hours
Cranium ultrasound wave irradiation, while by tail vein injection SonoVue.
Then, blood brain screen is detected by the leakage and Cerebral cortex Evans blue fluorescence of brain tissue Evans blue dyestuff respectively
Hinder permeability, transmission electron microscope detects the survey of cerebrovascular ultra microstructure, HE dyeing detection histopathology morphology and brain water content
It is fixed.
Wherein, the building of cerebral ischemia re-pouring model is specific as follows：ICR mouse pre-operative anxiety 6h, first with the different of 5% concentration
Fluothane induced anesthesia mouse, mouse fiber crops lower isoflurane concentration to 2% to maintain narcosis afterwards.After mouse anesthesia, lie on the back
Position is fixed on surgical plate, adjusts disecting microscope visual area, and sterilize mouse skin of neck with 75% ANER DIAN.Under microscope
Neck midsection skin, notch are about 1cm, each layer tissue of blunt separation, find salivary gland, tracheae level, blunt separation, cruelly
Reveal right carotid (CCA), internal carotid (ICA) and external carotid artery (ECA), carefully separation avoids damage to vagus nerve in art
And tracheae.From CCA intersect downwards separation, with 6-0 silk thread ligature CCA proximal part, and CCA distal end with silk thread make a call to a untwisting with
Just fixed after the insertion of line bolt；Then a slip-knot is made a call in CCA crotch using silk thread, lifts silk thread with a vessel forceps with Basilar artery
CCA bifurcated distant place blood reflux.A V-type osculum is cut off between 2 silk threads below the arteria carotis communis with microscissors, and bolt line is inserted
Enter, slightly then unlocks the silk thread that CCA crotch is used for Basilar artery after tie-down CCA distal end untwisting, further by bolt line
Push inward is until feel to stop inlet wire when light resistance, slightly toward the offline bolt of pumpback, and by the knot of CCA distal end to tie-down.
It cuts and is exposed to outer too long line bolt with silk thread, after visual area is cleaned with physiological saline, postoperative mouse is put by layer-by-layer suture
It is equipped on constant-temp. cushion and keeps the temperature.Again anesthetized mice after 1h is opened after 75% alcohol disinfecting of cervical incision, line bolt is gently pulled out
Stump is ligatured after out, cuts off extra silk thread, layer-by-layer suture, and alcohol sterilizes skin of neck again.Postoperative mouse is put into and is set
There is heat preservation on constant-temp. cushion until putting back in mouse cage again after revival.
The specific implementation process of ultrasound targeted microbubble bursting technologies (UTMD) is as follows：Mouse is through 1% yellow Jackets
After (30mg/Kg) intraperitoneal injection of anesthesia, calvarium portion loses hair or feathers through electric hair cutter and depilatory cream, is fixed on mouse stereoscopic localized with prone position
On instrument.As ultrasound wave irradiation region and it is coated with ultrasonic coupling agent using mouse brain right hemisphere temporo side, fills the annular water tank of deionized water
The semielliptical shape polyurethane film of bottom is aligned after the irradiation zone, and the bearing fixing clamp fixed vertical through bedside protrudes into sink
Ultrasonic probe.Ultrasonic probe connects medical ultrasonic equipment, and setting irradiation parameters are real-time radiography Flash mode, frequency
3.0MHz, depth of focus 5cm, low and high mechanical index (MI is respectively 0.06 and 1.0), intermittent time 2s always irradiate duration
3min.While ultrasound wave irradiation, 0.1ml SonoVue is slowly at the uniform velocity injected by tail vein, in the real-time contrastographic picture of ultrasound
Situation is perfused in upper observation SonoVue, and implements Flash ultrasound wave irradiation under its guidance.
It will be compareed between each group, result of study is as follows：
Fig. 1 is each group mouse Evans blue dyestuff leakage scenarios.(a) model group；(b) model+borneol group；(c) model+
UTMD group；(d) model+borneol+UTMD group.(A) leakage of each group mouse brain surface Evans blue；(B) each group right side of mice brain
Tissue Evans Blue leakage quantifies histogram；(C) each group mouse Cerebral cortex leaks Evans blue fluorescence detection；(D) each group mouse
The statistical analysis of Cerebral cortex leakage Evans blue fluorescence intensity.Illustrate that borneol reduces ultrasound targeted microbubble bursting technologies
(UTMD) the Evans blue dyestuff leakage induced.
Fig. 2 is the transmission electron microscope photo of each group mouse Cerebral cortex capillary.(A1) model group；(B1) model+borneol group；
(C1) model+UTMD group；(D1) model+borneol+UTMD group.Micrograph 2 is the enlarged drawing of 1 part of micrograph.EC：Endothelium is thin
Born of the same parents；TJ：Close connection；R：Red blood cell；CA：Alveole.Illustrate that borneol can weaken ultrasound targeted microbubble bursting technologies (UTMD) and lead
The opening of the cerebral microvascular ultra microstructure of cause.
Fig. 3 A is each group mouse brain cortex tissue morphology.(a) model group；(b) model+borneol group；(c) model+UTMD
Group；(d) model+borneol+UTMD group.Fig. 3 B is the statistical analysis of each group mouse brain cortical hemorrhage size.Illustrate borneol
Reduce cerebral hemorrhage caused by ultrasound targeted microbubble bursting technologies (UTMD).
Fig. 4 is the quantitative histogram of each group mouse infarct side brain water content.It is micro- to illustrate that borneol reduces ultrasound targeting
Steep the increase of brain water content caused by bursting technologies (UTMD).
The above results show borneol combined U TMD, can reduce further opening of the UTMD to cerebral ischemia blood-brain barrier, from
And safer strategy is provided as the complementary Neuroprotective Therapy in Treating Acute of Post stroke for UTMD.Borneol can be used as active constituent system
The standby drug for mitigating ultrasound targeted microbubble bursting technologies induction focal cerebral ischemia Blood Brain Barrier (BBB) opening.
Claims (3)
1. borneol is as living in the drug for mitigating ultrasound targeted microbubble bursting technologies induction focal cerebral ischemia Blood Brain Barrier (BBB) opening
The application of property ingredient.
2. application as described in claim 1, the structural formula of the borneol are shown below：
3. application as claimed in claim 1 or 2, it is characterised in that：The effective dose of borneol is 200mg/Kg weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810767540.0A CN108888612A (en) | 2018-07-13 | 2018-07-13 | Application of borneol as active ingredient of medicine for relieving opening of blood brain barrier caused by focal cerebral ischemia induced by ultrasonic targeted microbubble disruption technology |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810767540.0A CN108888612A (en) | 2018-07-13 | 2018-07-13 | Application of borneol as active ingredient of medicine for relieving opening of blood brain barrier caused by focal cerebral ischemia induced by ultrasonic targeted microbubble disruption technology |
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| Publication Number | Publication Date |
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| CN108888612A true CN108888612A (en) | 2018-11-27 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232347A (en) * | 2013-04-12 | 2013-08-07 | 合肥工业大学 | A brain targeting prodrug for CNS (central nervous system) drugs and a preparation method thereof, and applications of borneol in the brain targeting prodrug for CNS drugs |
| CN105879036A (en) * | 2016-04-14 | 2016-08-24 | 成都大学 | Application of composition containing borneol and drug loaded nanoparticles in treatment of cerebral diseases |
-
2018
- 2018-07-13 CN CN201810767540.0A patent/CN108888612A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232347A (en) * | 2013-04-12 | 2013-08-07 | 合肥工业大学 | A brain targeting prodrug for CNS (central nervous system) drugs and a preparation method thereof, and applications of borneol in the brain targeting prodrug for CNS drugs |
| CN105879036A (en) * | 2016-04-14 | 2016-08-24 | 成都大学 | Application of composition containing borneol and drug loaded nanoparticles in treatment of cerebral diseases |
Non-Patent Citations (1)
| Title |
|---|
| XIAO-GUANG ZHANG ET AL.: "Borneol attenuates Ultrasound-Targeted Microbubble Destructioninduced Blood–Brain Barrier Opening in Focal cerebral ischemia", 《FRONTIERS IN NEUROLOGY》 * |
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Application publication date: 20181127 |