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Applications of tetramethylpyrazine derivative tetramethylpyrazine nitrone to prevention and treatment of brain injury diseases

A nitroxazine and brain injury technology, applied in the field of ligustrazine derivatives, can solve the problems of difficulty in passing through the blood-brain barrier, failure, NXY-059 does not achieve the expected therapeutic effect, etc., and achieves significant neuroprotection and blood-brain barrier. The effect of improving ability and preventing brain damage diseases

Active Publication Date: 2016-09-28
GUANGZHOU MAGPIE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A large number of preclinical animal experiments and phase II clinical trials and the first phase III clinical trial have proved that NXY-059 has a good therapeutic effect on ischemic stroke, but the second phase III clinical trial, NXY-059 has no One of the reasons for its failure may be related to its difficulty in passing the blood-brain barrier

Method used

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  • Applications of tetramethylpyrazine derivative tetramethylpyrazine nitrone to prevention and treatment of brain injury diseases
  • Applications of tetramethylpyrazine derivative tetramethylpyrazine nitrone to prevention and treatment of brain injury diseases
  • Applications of tetramethylpyrazine derivative tetramethylpyrazine nitrone to prevention and treatment of brain injury diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1. The effect of nitroxazine on the behavior of TBI rats

[0038] The rat TBI model was established by PCI3000 instrument, and 90 mg / kg nitroxazine was injected into the tail vein twice a day at 3h, 6h and day2-day7 after operation, and behavioral scores were performed at 3h, 24h, 72h, 5d, and 8d after operation, respectively. (Rotary bar test, paper strip adhesion test, NSS behavioral score, balance beam test).

[0039] Rotarod test: A rotarod was used during the test, and SD rats were recorded every day when the roller accelerated from 6 rpm to 30 rpm (every 5 rpm, with an interval of 10s, until 30 rpm, and kept to the end , the process is 120s) the time that the axis does not fall. Do the next test every 15 minutes, 2 times in total. The animals were trained 3 days in advance before modeling, and the rats that stayed on the rod for more than 75 s were included in the experimental group.

[0040] Paper stick adhesion experiment: use a paper strip to make a ...

Embodiment 2

[0047] Example 2. The effect of nitroxazine on the histological changes of the cerebral infarction area in TBI rats

[0048] On the 8th day after the operation, perfusion and internal fixation were performed, and the brain tissue was taken out for further fixation, dehydration, and paraffin embedding. The process is as follows: 1) Xylene dewaxing and transparent: 5 minutes each time, 2 times each; 2) Alcohol gradient elution: 100% alcohol (5 minutes); 100% alcohol (2 minutes); 95% alcohol (2 minutes); 95% alcohol (2min); 3) Washing slides with distilled water: deionized water, 1min; 4) Hematoxylin staining for 15min, 37°C; 5) Washing slides: Washing slides with water for 30s; 6) Differentiation: Differentiation with 1% hydrochloric acid alcohol for 3s; 7) Washing slides : Rinse with running water for 10-20min (12min), this step is to promote blue; 8) Eosin staining: 0.5% eosin staining for 15min, 37 ℃; 9) Alcohol hydration: sequentially at 70%, 80%, 95%, 100 %, 100%, 100% alc...

Embodiment 3

[0049] Example 3. Effects of nitroxazine on the expression changes of neurons, glial fibrillary acidic protein, 4-hydroxynonenal and 8-hydroxydeoxyguanosine in TBI rats

[0050] On the 8th postoperative day, perfusion and internal fixation were performed, and the brain tissue was taken out for further fixation, dehydration and paraffin-embedding, and paraffin-immunohistochemical staining was performed after making sections. The process is as follows: 1) Xylene dewaxing and transparent: 10min each time, 2 times; 2) Gradient elution: 100% ethanol (5min); 100% ethanol (2min); 95% ethanol (2min); 95% ethanol (2min) ); rinsed with deionized water; 3) Antigen retrieval of slices: slices were repaired using citric acid buffer (pH=6.0) microwave method for antigen retrieval (5min on high heat, 10min on medium-low heat), and naturally cooled to room temperature; 4) Washing with TBS Slides: wash slides with 1*TBS, 3 min each time, 3 times in total; 5) 3% H 2 O 2 (TBS configuration) Bl...

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Abstract

The invention belongs to the field of medicament technology, and especially relates to applications of a tetramethylpyrazine derivative tetramethylpyrazine nitrone to medicament preparation as well as prevention and treatment of brain injury diseases. Experiments prove that tetramethylpyrazine nitrone can improve traumatic brain injury and brain injury after subarachnoid hemorrhage; the improvements concretely comprise the following aspects: improvement of behaviors of model rats with traumatic brain injury and subarachnoid hemorrhage, reduction of cerebral infarction areas due to traumatic brain injury, improvement of vasospasm state after subarachnoid hemorrhage, and protection of brain tissues. Mechanisms of action of tetramethylpyrazine nitrone relate to inhibition of oxidative stress injuries, inhibition of inflammatory reactions, and apoptosis resistance. Tetramethylpyrazine nitrone can be used as a medicine for preventing and treating brain injury diseases, especially traumatic brain injury and subarachnoid hemorrhage, and can be prepared into various dosage forms with medicinal carriers.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to the application of nitroxazine, a ligustrazine derivative, in preventing and treating brain injury diseases, especially in preparing medicines and preventing and treating traumatic brain injury and subarachnoid hemorrhage diseases. Background technique [0002] Traumatic brain injury (TBI), also known as intracranial injury, is a common disease in neurosurgery, and is recognized as one of the frequently-occurring and refractory injuries. A large number of studies have confirmed that the brain dysfunction after TBI is not only caused by the primary injury such as the initial mechanical external force, but also is largely related to the complex neuron "second hit" that occurs after the injury. Neuronal injury is related to the mechanism of calcium overload, excitatory amino acid toxicity, mitochondrial dysfunction, oxidative stress, apoptosis and inflammatory response. [0003] As ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4965A61P25/00A61P7/04A61P9/00
CPCA61K31/4965
Inventor 王玉强孙业伟张在军于沛张高小易鹏
Owner GUANGZHOU MAGPIE PHARMA
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