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Application of ramelteon in preparation of drug for treating ischemic brain injury

A technology for ischemic brain injury and ischemic stroke, which is applied in the field of drug therapy and can solve problems such as unclear anti-ischemic effects

Inactive Publication Date: 2018-09-18
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recent studies have found that melatonin receptors may be an important new target for cerebral ischemia drug treatment. The affinity of ramelteon to melatonin receptors is more than 17 times that of melatonin itself, but ramelteon Whether it has a potential anti-ischemic effect is still unclear, and so far there have been no relevant studies and reports on the use of ramelteon or its analogues in the treatment of ischemic stroke or cerebral infarction

Method used

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  • Application of ramelteon in preparation of drug for treating ischemic brain injury
  • Application of ramelteon in preparation of drug for treating ischemic brain injury
  • Application of ramelteon in preparation of drug for treating ischemic brain injury

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: The dose-dependent effect of ramelteon on permanent cerebral ischemic injury

[0023] Mouse model of permanent cerebral ischemia

[0024] For focal cerebral ischemia, the middle cerebral artery (MCAO) of C57BL / 6 mice was blocked by suture method. The branches of the external carotid artery were ligated and cut off, and the thread was inserted into the ring of William's to block the beginning of the middle cerebral artery. In the sham operation group, the nylon thread was only inserted about 0.5 cm, and the thread was left for 24 hours. At the same time, Doppler laser cerebral blood flowmeter was used to monitor the blood flow in the infarcted brain area, and the animals whose blood flow dropped below 20% of the baseline value after ischemia were selected.

[0025] Neurological symptom score and calculation of cerebral infarction volume

[0026] The degree of neurological damage was evaluated by neurological symptom score; the infarct volume was calculated b...

Embodiment 2

[0028] Example 2: The optimal administration time window of ramelteon against permanent cerebral ischemic injury

[0029] Using the pMCAO model, 3 mg / kg ramelteon was administered at different time points (0h, 4h, 6h) after pMCAO model establishment, and the neurological symptoms of each group of animals at different time points after ischemia were investigated and scored. After the brain was removed, the volume of cerebral infarction was measured by TTC staining method. The results showed that administration within 6 hours after cerebral ischemia in mice could significantly reduce the volume of cerebral infarction ( figure 2 ), suggesting that 0-6h after acute cerebral ischemia is the best administration time window for ramelteon treatment. *P<0.05, **P<0.05v.s pMCAO group (n=6)

Embodiment 3

[0030] Example 3: MT 2 Melatonin receptor inhibitor 4-P-PDOT effectively inhibits the brain protection of ramelteon

[0031] Using the pMCAO model, preoperative intraperitoneal injection of specific MT 2 The melatonin receptor inhibitor 4-P-PDOT was given ramelteon by intragastric administration, and the neurological symptoms of animals in each group were observed and scored after 24 hours of ischemia. After the brain was removed, the volume of cerebral infarction was measured by TTC staining method. As a result, it was found that the cerebral infarction volume and neurological symptom scores of mice given 4-P-PDOT and ramelteon were significantly greater than those of ramelteon alone ( image 3 ), suggesting that 4-P-PDOT can effectively inhibit the anti-ischemic effect of ramelteon. *P<0.05v.s ramelteon administration group (n=6)

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Abstract

The invention discloses application of ramelteon in preparation of a drug for treating ischemic brain injury. Ramelteon can alleviate acute focal cerebral ischemic injury and neurological dysfunctioncaused by permanent middle cerebral artery embolization in mice, inhibit pathological inflammatory response, and promote neural functional recovery in the late stage of ischemia. The use of ramelteonis achieved primarily by the following mechanism: ramelteon can inhibit cell autophagy during cerebral ischemia and reduces autophagic death of neurons by stimulating the MT2 melatonin receptor; in addition, ramelteon can also inhibit the release of inflammatory factors secondary to cerebral ischemia, reduce inflammatory cell damage, and ultimately exert a therapeutic effect against cerebral ischemia. The application provided by the invention has the beneficial effects of providing a new use of ramelteon, and providing a basis for screening new drugs.

Description

technical field [0001] The invention belongs to the field of drug therapy, and in particular relates to the related application of ramelteon in the preparation of drugs for treating ischemic brain injury. Background technique [0002] Stroke is a type of cerebrovascular disease caused by cerebral blood supply disorder and characterized by rapid focal loss of brain function. According to statistics, about 87% of all stroke types are ischemic stroke, and its pathophysiological mechanism is extremely complex. In clinical practice, there is no better treatment method except thrombolysis within a short time after ischemia. However, the time window for thrombolysis is narrow, and most patients unfortunately miss the golden treatment period after cerebral ischemia due to various reasons, and then form permanent ischemic lesions, affecting normal neurological function. Therefore, it is urgent to find important pathological links and effective drug regulation targets after cerebral ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/343A61P9/10A61P25/00
CPCA61K31/343A61P9/10A61P25/00
Inventor 吴佳莹洪东升卢晓阳
Owner ZHEJIANG UNIV
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