CN115364098A - Application of YL-IPA08 in preparation of medicine for repairing functions after ischemic stroke - Google Patents
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- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
The invention discloses application of YL-IPA08 in preparation of a medicine for repairing functions after ischemic stroke. The novel TSPO agonist YL-IPA08 with high affinity with TSPO has good water solubility, high bioavailability and no benzodiazepine, is easy to permeate blood brain barrier
Like side effects, the research of the invention finds that the TSPO agonist YL-IPA08 has obvious neuroprotective effect.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of YL-IPA08 in preparation of a medicine for repairing functions after ischemic stroke.
Background
Stroke (stroke) is an acute cerebrovascular disease in which the blood rheology is altered by the blockage or rupture of blood vessels, which in turn causes brain injury. The Chinese stroke incidence is one of the countries with the highest worldwide incidence, the cerebral stroke disability rate is about 75 percent, and the Chinese stroke disability rate is the first cause of disability of adults in China. Stroke places a heavy burden on people and society in our country.
Clinically, the more effective treatment of acute ischemic stroke is recanalization. But because of the narrow time window of treatment, few patients can benefit from this. The second is a cerebroprotective agent treatment, but neuroprotective agents present some clinical transformation disorders. There is no treatment scheme and drug effective in promoting post-stroke brain recovery or improving long-term prognosis, and even if thrombolytic in time, the neurological damage after ischemia cannot be significantly improved. Therefore, the search for effective therapeutic drugs for ischemic stroke and the promotion of the functional recovery of cranial nerves after stroke are scientific problems to be solved urgently at present.
The 18KD Translocator Protein (TSPO) is located predominantly on the outer mitochondrial membrane of glial cells in the brain. Under physiological conditions, the expression level of TSPO in the central nervous system is very low, but under certain pathological conditions, TSPO expression increases in activated microglia and astrocytes, and is more significantly expressed in activated microglia in particular. Early laboratory studies found that a large number of microglia were activated after stroke, whereas TSPO was highly expressed on all activated microglia subpopulations.
Disclosure of Invention
The invention aims to provide application of YL-IPA08 in preparation of a medicine for repairing functions after ischemic stroke.
Application of YL-IPA08 in preparation of medicines for functional repair after ischemic stroke.
The molecular formula of YL-IPA08 is as follows:
a medicine for treating ischemic apoplexy contains YL-IPA08 as active ingredient.
Preferably, the composition further comprises one or more pharmaceutically acceptable auxiliary materials or carriers.
The adjuvants or carriers include diluent, excipient, filler, binder, humectant, disintegrating agent, absorption enhancer, surfactant, adsorption carrier or lubricant.
The pharmaceutical composition can be prepared into dosage forms of tablets, capsules, effervescent tablets, granules, powder, dispersible tablets, oral liquid, pills or injections.
The invention has the beneficial effects that: the TSPO agonist Etifoxine has certain neuroprotective effect in the central nervous system, but has low solubility, can reduce neuron excitability, and has benzodiazepines with sedation, muscle relaxation, withdrawal response, cognitive impairment and the like
Like side effects, the novel TSPO agonist YL-IPA08 with high affinity to TSPO has good water solubility, easy blood brain barrier penetration, high bioavailability and no benzodiazepine
Like side effects, the research of the invention finds that the TSPO agonist YL-IPA08 has obvious neuroprotective effect.
Drawings
FIG. 1 shows the effect of YL-IPA08 on infarct volume in PT model mice.
FIG. 2 shows the effect of YL-IPA08 on sensory-motor function of PT model mice.
FIG. 3 is a graph of the effect of YL-IPA08 on infarct volume in dMCAO model mice.
Fig. 4 is a graph of the determination of YL-IPA08 dosing time window for the dcao model.
FIG. 5 shows the behavioral effects of YL-IPA08 on dMCAO model mice.
Detailed Description
In order that the invention may be more fully understood, reference will now be made to the following description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
The following examples use experimental materials: 7-8 week old C57BL/6J mice, male, SPF grade, initial weight 25-30g, purchased from Jiangsu Jiejiekang Biotech GmbH, license number: SCXK (su) 2018-0008.YL-IPA08 (99% purity, synthesized by institute of poison drugs, academy of military medical sciences). Edaravone (3-Methyl-1-phenyl-2-pyrazoline-5-one from sigma) was used as a positive drug.
Example 1 Effect of YL-IPA08 on infarct volume in Photochemosensitive (PT) acute ischemic stroke model mice
Establishment of photochemical sensitive (PT) acute ischemic stroke model:
(1) Mice were anesthetized in a closed anesthesia chamber containing 3% isoflurane, 30% oxygen, and 70% carbon dioxide;
(2) 30mg/Kg of rose bengal is injected into tail vein;
(3) Fixing the mouse in a brain stereotaxic apparatus, removing hair on the head of the mouse, cutting off the scalp, and confirming the Bregma position;
(4) Moving the optical fiber to the position 1.5mm away from Bregma, illuminating for 5min by a cold light source, and then 12000Lux;
(5) Suturing the scalp of the mouse, and smearing iodophor to prevent infection;
(6) The mice were placed on a 37 ℃ constant temperature blanket and were placed in the mouse cage after the mice recovered.
Small animal Magnetic Resonance Imaging (MRI):
(1) The mice were anesthetized with 2% isoflurane continuously and the respiratory rate of the mice was monitored by a physiological monitor;
(2) Coronary T2 weighted imaging was used, with the coil placed above the rat brain (except for the olfactory bulb). T2WI sequence:
repetition time =2500ms, echo time =33ms, number of layers =12, layer thickness =1mm, layer spacing =1mm, matrix =256 × 256, fov =20mm × 20mm;
(3) Quantification of MRI images using Image J software, high signal region acquisition based on T2-weighted images
Lesion volume. Image J counts infarct size, infarct size (mm 2) = healthy side size (mm 2) -injured side non-infarct size (mm 2).
Grouping: blank control group; a model control group; model + YL-IPA08 (0.1 mg/Kg); model + YL-IPA08 (0.3 mg/Kg); model + YL-IPA08 (1 mg/Kg).
4) Administration: YL-IPA08 was administered 1h after molding, by tail vein injection (i.v.), 1 time/day, for 3 consecutive days.
5) And (4) data statistical processing, wherein the software GraphPad Prism 8.0.2 is used for statistical analysis. The two sets of data were assessed for differences using Student's t (two-sided) test or Mann-Whitney U test; three and more groups of differences are evaluated by adopting one-factor variance analysis, and the subsequent test adopts Holm-Sidak. The significance difference criterion was P < 0.05. The results are shown in figure 1, and the infarct volume of the mice model of acute ischemic stroke is reduced after administration.
Example 2 behavioral Effect of YL-IPA08 on PT model mice
And (3) environmental adaptation: within 3 days of acclimatization, mice were gently grabbed for 3 minutes each day in order to reduce the effect of irrelevant stress stimuli on subsequent experimental manipulations. In the experimental process, the relative silence of the experimental environment is ensured. All mice were kept in a cage with free diet and drinking water, and the light was controlled to alternate day and night for 12 hr.
A training period:
each mouse walks for 5min on a grid of 12mm2 of 32cm × 20cm × 50cm (length × width × height), and each mouse is trained 3 times a day for 3 consecutive days.
Each mouse was placed in a transparent resin cylinder of 9cm diameter and 15cm height for 5min, and each mouse was trained 3 times a day for 3 consecutive days.
And (3) sticking circular labels with the diameter of 5mm to the radius at the far end of the wrist joint of the forelimb at the two sides of the mouse, and tearing off the adhesive paper. Each mouse was trained 3 times a day for 3 consecutive days.
Establishment of photochemical sensitive (PT) acute ischemic stroke model:
(1) Mice were anesthetized in a closed anesthesia chamber containing 3% isoflurane, 30% oxygen, and 70% carbon dioxide;
(2) Tail vein injection rose bengal 30mg/Kg;
(3) Fixing the mouse in a brain stereotaxic apparatus, removing hair on the head of the mouse, cutting off the scalp, and confirming the Bregma position;
(4) Moving the optical fiber to the position 1.5mm away from Bregma, illuminating for 5min by a cold light source, and then 12000Lux;
(5) Suturing the scalp of the mouse, and smearing iodophor to prevent infection;
(6) The mice were placed on a 37 ℃ constant temperature blanket and were placed in the mouse cage after the mice recovered.
Grouping: blank control group; a model control group; model + YL-IPA08 (0.1 mg/Kg,3 h); model + YL-IPA08 (0.1 mg/Kg,6 h); model + YL-IPA08 (0.1 mg/Kg,12 h); model + YL-IPA08 (0.1 mg/Kg,24 h).
Administration: after 3h,6h,12h and 24h, YL-IPA08 is administered by tail vein injection (i.v.), and the administration dose is 0.1mg/Kg,1 time/day, and the continuous administration is 14 days.
And (3) behavioral detection:
grid test: the mice are placed on a grid of 12mm2 with the length multiplied by 20cm multiplied by 50cm (the length multiplied by the width multiplied by the height), and the error frequency within 100 steps of walking of the left forelimb of the mice is recorded after 1min of adaptation. The following two cases are considered as walking errors: 1) The left forelimb of the mouse penetrates into the grid hole and cannot support the body; 2) When the mouse is at rest, the left forelimb wrist is level with the grid. Mouse left forelimb error percentage (%) = left forelimb error number/(left forelimb error number + left forelimb correct step number) × 100%.
Cylinder test: the mice were placed in a transparent resin cylinder 9cm in diameter and 15cm in height and recorded for 5min by video recording. When the mouse stands, the times of the right forelimb, the left forelimb and the bilateral forelimbs touching the cylinder wall at the same time are respectively recorded. Mice scored in this trial = (right forelimb-left forelimb)/(right forelimb + left forelimb + bilateral forelimb) number of contacts, with higher scores indicating more pronounced bilateral limb asymmetry.
Adhesion-removal test (i.e. pick test): circular labels with the diameter of 5mm are attached to the radius at the far end of the wrist joint of the forelimb on the two sides of the mouse, and the time for removing the labels from the forelimb on the two sides of the mouse is recorded respectively. If the mouse failed to remove the tag within 2min, the sticker was deemed not removable. Evaluation formula of mouse sensorimotor function asymmetry: delay time (sec) = time of left front limb removal tag (sec) -time of right front limb removal tag (sec).
And (3) data statistical processing, wherein the software GraphPad Prism 8.0.2 is used for statistical analysis. The two sets of data were assessed for differences using Student's t (two-sided) test or Mann-Whitney U test; three or more groups of differences are evaluated by adopting one-factor variance analysis, and the later test adopts Holm-Sidak. The significance difference standard is P < 0.05. The results are shown in FIG. 2.
Example 3 Effect of YL-IPA08 on infarct volume in the mouse distal median arterial occlusion model (dMCAO)
Establishment of a distal mid-artery occlusion model (dmco):
(1) Mice were initially anesthetized in a closed anesthesia chamber containing 3% isoflurane, 30% oxygen and 70% carbon dioxide;
(2) Keeping 1.5% isoflurane continuously ventilating to maintain the mouse anesthesia state, fixing the mouse in the right lateral decubitus position, and smearing erythromycin ointment on two eyes;
(3) A 1cm incision is made at the connecting line of an inner canthus and an outer auditory canal, muscle tissues attached to a temporal bone are cut and separated, and a skull drill grinds a skull until a Middle Cerebral Artery (MCA) is completely exposed;
(4) Washing the wound surface with normal saline, and removing residual bone fragments with surgical micro forceps;
(5) Electrocoagulation is carried out on MCA trunk by bipolar electric coagulation forceps for 30sec, and if the MCA is still blood-supplied, electrocoagulation is carried out again until the MCA trunk is completely blocked;
(6) Resetting the muscle tissue, suturing the incision and smearing the incision with iodophor;
(7) Placing mouse on constant temperature blanket at 37 deg.C for waking up, and feeding for 24 hr;
(8) The blank control mice were operated identically except for the absence of electrocoagulated MCA trunk.
TTC (2, 3, 5-triphenyltetrazolium chloride) dye:
(1) On day 3 after molding, mice were anesthetized in a closed anesthetic chamber containing 3% isoflurane, 30% oxygen, and 70% carbon dioxide;
(2) Fixing the mouse, lying on the back, cutting the chest of the mouse, inserting a needle communicated with a constant flow pump into the left ventricle of the mouse, cutting open the right auricle, draining, and perfusing with 250mL of 0.01mol/L PBS;
(3) Taking out mouse brain, and freezing at-20 deg.C for 10min;
(4) Slicing the rat brain by using a self-made row knife, and placing the last blade at a lambda point;
(5) Placing brain slices into a six-well plate containing 1% TTC solution;
(6) Incubating at 37 deg.C for 2min on the front and back of brain slice;
(7) Fixing brain slice in PFA solution at 4% (v/v), and keeping away from light at 4 deg.C for 12 hr;
(8) The centimeter ruler is used as a scale, and the picture is taken on a black frosted background plate.
Grouping: blank control group; a model control group; model + YL-IPA08 (0.1 mg/Kg); model + YL-IPA08 (0.3 mg/Kg); model + YL-IPA08 (1 mg/Kg).
Administration: YL-IPA08 was administered 1h after molding, by tail vein injection (i.v.), 1 time/day, for 3 consecutive days.
Data statistics processing, namely quantitatively counting the infarct area (mm) by using Image J software 2 ) = healthy lateral area (mm) 2 ) -area of non-infarct on the side of injury (mm) 2 )。
Statistical analysis was performed using GraphPad Prism 8.0.2 software. The two sets of data were assessed for differences using Student's t (two-sided) test or Mann-Whitney U test; three and more groups of differences are evaluated by adopting one-factor variance analysis, and the subsequent test adopts Holm-Sidak. The significance difference standard is P < 0.05. The results are shown in FIG. 3.
Example 4 YL-IPA08 dosing time window was determined on a mouse distal median arterial occlusion model (dMCAO)
Establishment of a distal mid-artery occlusion model (dmco):
(1) Mice were initially anesthetized in a closed anesthesia chamber containing 3% isoflurane, 30% oxygen and 70% carbon dioxide;
(2) Keeping 1.5% isoflurane continuously ventilating to maintain the mouse anesthesia state, fixing the mouse in the right lateral decubitus position, and smearing erythromycin ointment on two eyes;
(3) A 1cm incision is made at the connecting line of an inner canthus and an outer auditory canal, muscle tissues attached to a temporal bone are cut and separated, and a skull drill grinds a skull until a Middle Cerebral Artery (MCA) is completely exposed;
(4) Washing the wound surface with normal saline, and removing residual bone fragments with surgical micro forceps;
(5) Electrocoagulation of MCA trunk by bipolar coagulation forceps is carried out, after 30sec, MCA blood supply is observed, if blood supply still exists, electrocoagulation is carried out again until MCA trunk is completely blocked;
(6) Resetting muscle tissue, suturing the incision and smearing the wound with iodophor;
(7) Placing mouse on constant temperature blanket at 37 deg.C for waking up, and feeding for 24 hr;
(8) The blank control mice were operated identically except without electrocoagulation of the MCA trunk.
TTC (2, 3, 5-Triphenyltetrazolium chloride) dye:
(1) On day 3 after molding, mice were anesthetized in a closed anesthetic chamber containing 3% isoflurane, 30% oxygen, and 70% carbon dioxide;
(2) Fixing the mouse, lying on the back, cutting the thoracic cavity of the mouse, inserting a needle communicated with a constant flow pump into the left ventricle of the mouse, cutting open the right auricle for liquid discharge, and perfusing with 250mL of 0.01mol/L PBS;
(3) Taking out mouse brain, and freezing at-20 deg.C for 10min;
(4) Slicing the rat brain by using a self-made row knife, and placing the last blade at a lambda point;
(5) Placing brain slices into a six-well plate containing 1% TTC solution;
(6) Incubating at 37 deg.C for 2min on the front and back of brain slice;
(7) Fixing brain slice in PFA solution at 4% (v/v), and keeping away from light at 4 deg.C for 12 hr;
(8) The centimeter ruler is used as a scale, and the picture is taken on a black frosted background plate for imaging.
Grouping: blank control group; a model control group; model + YL-IPA08 (0.1 mg/Kg,3 h); model + YL-IPA08 (0.1 mg/Kg,6 h); model + YL-IPA08 (0.1 mg/Kg,12 h); model + YL-IPA08 (0.1 mg/Kg,24 h).
Administration: after molding 3h,6h,12h and 24h, YL-IPA08 was administered by tail vein injection (i.v.), at a dose of 0.1mg/Kg,1 time/day, continuously for 3 days
Data statistics processing, namely quantitatively counting the infarct area (mm) by using Image J software 2 ) = healthy lateral area (mm) 2 ) -area of non-infarct on the side of injury (mm) 2 )。
Statistical analysis was performed using GraphPad Prism 8.0.2 software. The two sets of data were assessed for differences using Student's t (two-sided) test or Mann-Whitney U test; three or more groups of differences are evaluated by adopting one-factor variance analysis, and the later test adopts Holm-Sidak. The significance difference standard is P < 0.05. The results are shown in FIG. 4.
Example 5 behavioral Effect of YL-IPA08 on dMCAO model mice
And (3) environmental adaptation: within 3 days of acclimatization, the mice were gently grabbed for 3 minutes each day in order to reduce the effect of irrelevant stress stimuli on the subsequent experimental manipulations. In the experimental process, the relative silence of the experimental environment is ensured. All mice live in a cage with free diet and drinking water, and the light irradiation was controlled to alternate day and night for 12 hr.
A training period: each mouse walks for 5min on a grid of 12mm2 of 32cm × 20cm × 50cm (length × width × height), and each mouse is trained 3 times a day for 3 consecutive days.
Each mouse was placed in a transparent resin cylinder of 9cm diameter and 15cm height for 5min, and each mouse was trained 3 times a day for 3 consecutive days.
And (3) sticking circular labels with the diameter of 5mm to the radius at the far end of the wrist joint of the forelimb at the two sides of the mouse, and tearing off the adhesive paper. Each mouse was trained 3 times a day for 3 consecutive days.
Establishment of a distal mid-artery occlusion model (dmco):
(1) Mice were initially anesthetized in a closed anesthesia chamber containing 3% isoflurane, 30% oxygen and 70% carbon dioxide;
(2) Keeping 1.5% isoflurane continuously ventilating to maintain the mouse anesthesia state, fixing the mouse in the right lateral decubitus position, and smearing erythromycin ointment on two eyes;
(3) A 1cm incision is made at the connecting line of the inner canthus and the external auditory canal, muscle tissues attached to the temporal bone are cut and separated, and a skull drill grinds the skull until the Middle Cerebral Artery (MCA) is completely exposed;
(4) Washing the wound surface with normal saline, and removing residual bone fragments with surgical micro forceps;
(5) Electrocoagulation is carried out on MCA trunk by bipolar electric coagulation forceps for 30sec, and if the MCA is still blood-supplied, electrocoagulation is carried out again until the MCA trunk is completely blocked;
(6) Resetting the muscle tissue, suturing the incision and smearing the incision with iodophor;
(7) Placing the mice on a constant temperature blanket at 37 deg.C for waking up, and feeding for 24 hr;
(8) The blank control mice were operated identically except for the absence of electrocoagulated MCA trunk.
Grouping: blank control group; a model control group; model + edaravone (6 mg/Kg); model + YL-IPA08 (0.1 mg/Kg).
Administration: the administration is started 24h after the molding is finished, the administration mode is tail vein injection (i.v.), the administration dose is 0.1mg/Kg,1 time/day, and the administration is continuously carried out for 14 days.
And (3) behavioral detection:
grid test: the mice are placed on a grid of 12mm2 with the length multiplied by 20cm multiplied by 50cm (the length multiplied by the width multiplied by the height), and the error frequency within 100 steps of walking of the left forelimb of the mice is recorded after 1min of adaptation. The following two cases are considered as walking errors: 1) The left forelimb of the mouse penetrates into the grid hole and cannot support the body; 2) When the mouse is at rest, the left forelimb wrist is level with the grid. Mouse left forelimb error percentage (%) = left forelimb error number/(left forelimb error number + left forelimb correct step number) × 100%.
Cylinder test: the mice were placed in a transparent resin cylinder 9cm in diameter and 15cm in height and recorded for 5min by video recording. When the mouse stands, the times of the right forelimb, the left forelimb and the bilateral forelimbs touching the cylinder wall at the same time are respectively recorded. Mice scored in this trial = (right forelimb-left forelimb)/(right forelimb + left forelimb + bilateral forelimb) number of contacts, with higher scores indicating more pronounced bilateral limb asymmetry.
Adhesion-removal test (i.e. pick test): circular labels with the diameter of 5mm are attached to the radius at the far end of the wrist joint of the forelimb on the two sides of the mouse, and the time for removing the labels from the forelimb on the two sides of the mouse is recorded respectively. If the mouse failed to remove the tag within 2min, the sticker was deemed to be unable to be removed. Evaluation formula of mouse sensorimotor function asymmetry: delay time (sec) = time of left front limb removal tag (sec) -time of right front limb removal tag (sec).
And (4) data statistical processing, wherein the software GraphPad Prism 8.0.2 is used for statistical analysis. The two sets of data were assessed for differences using Student's t (two-sided) test or Mann-Whitney U test; three and more groups of differences are evaluated by adopting one-factor variance analysis, and the subsequent test adopts Holm-Sidak. The significance difference criterion was P < 0.05. The results are shown in FIG. 5.
The research of the above examples shows that on mouse PT and dMCAO stroke models, continuous tail vein injection of YL-IPA08 of the invention for 24h after stroke can obviously improve sensory and motor dysfunction of stroke mice, and has obvious neuroprotective effect.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (6)
- Application of YL-IPA08 in preparing medicine for repairing function after ischemic stroke is provided.
- 2. The use of YL-IPA08 according to claim 1 for preparing a medicament for post-ischemic stroke functional repair, wherein the formula of YL-IPA08 is as follows:
- 3. a medicine for treating ischemic stroke is characterized in that the active ingredient of the medicine is YL-IPA08.
- 4. The agent for treating ischemic stroke as claimed in claim 3, further comprising one or more pharmaceutically acceptable excipients or carriers.
- 5. The agent for treating ischemic stroke according to claim 4, wherein said excipient or carrier comprises diluent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, adsorptive carrier or lubricant.
- 6. The medicine for treating ischemic stroke according to claim 3, wherein the pharmaceutical composition can be prepared into the dosage forms of tablets, capsules, effervescent tablets, granules, powder, dispersible tablets, oral liquids, pills or injections.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102295642A (en) * | 2010-06-25 | 2011-12-28 | 中国人民解放军军事医学科学院毒物药物研究所 | 2-aryl imidazo [1,2-a] pyridine-3-acetamide derivative and preparation method as well as application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295642A (en) * | 2010-06-25 | 2011-12-28 | 中国人民解放军军事医学科学院毒物药物研究所 | 2-aryl imidazo [1,2-a] pyridine-3-acetamide derivative and preparation method as well as application thereof |
Non-Patent Citations (2)
| Title |
|---|
| LI-MING ZHANG ET AL: "Antidepressant-like and anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa)", 《NEUROPHARMACOLOGY》 * |
| 甘甜甜: "YL-IPA08对小鼠脑损伤后星形胶质细胞活化及神经元应激损伤的影响", 《中国优秀硕士学位论文全文数据库》 * |
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