| With the change of the human lifestyle and the increase of the social pressure, cerebral vascular diseases, which account for one of the three causes of death in human beings, has become a major threat to human health, in which the cerebral ischemic diseases account for a large proportion. Researchers has made a lot of discovery on the pathogenesis and the treatment of cerebral ischemic injury, and many theories has been put forward so far. However, because the pathogenesis of the disease is extremely complex, and the ideal drug hasn't been discovered yet, it is necessary for us to continue to make investigation.In recent years, oxidative stress and endoplasmic reticulum stress draw a wide range of attention of scientists. In pathological conditions, the body may creat excessive free radicals, and the antioxidant system may fail, which could undermine the balance of free radical metabolism. This is the so called oxidative stress. The attack of excess free radicals to body could lead to the tissue damage. In the condition of some physiological or biochemical stimulations, a large number of unfolded proteins and misfolded proteins are accumulating in the cavity of the endoplasmic reticulum, causing a series of responses. This is the so called endoplasmic reticulum stress. Severe endoplasmic reticulum stress could induce apoptosis and damage tissues. It has been found that oxidative stress and endoplasmic reticulum stress are relevant to cerebral ischemic injury. It provides clues for us to furtherly investigate the interventinal mechenism of drugs on cerebral ischemic injury.Oxymatrine (OMT) is a kind of quinolizidine alkaloid which is extracted and separated from some Traditional Chinese Medicine such as Sophora flavescens Ait. and Sophora alopecuroides L. which are widely distributed in North China. A large number of pharmacological studies have found that OMT has many biological acitivities such as anti-inflammation, anti-tumor, anti-fibrosis, anti-arrhythmia and anti-cerebral ischemic injury, etc. Our team has reported the interventional effects of OMT to cerebral ischemic injury, so it is an urgent issue to investigate whether there are relationship between the interventional effects and oxidative stress and endoplasmic reticulum stress.Objective:First of all, thread embolism method was utilized to make the focal cerebral ischemia model in rats. Then, the interventional effects of OMT on cerebral ischemia was investigated from the aspects of morphology, biochemistry and immuno- histochemistry. The last but not the least, the interventional mechanism of OMT on cerebral ischemia was revealed from the aspects of oxidative stress and endoplasmic reticulum stress.Methods:The experimental rats were randomly divided into model group, sham operation group, positive drug group, OMT1 (35mg·kg-1) group, OMT2 (70mg·kg-1) group and OMT3 (105mg·kg-1) group. The drug was continuously administrated 5 days before the surgery of middle cerebral artery occlusion (MCAO) was carried out. The indicators of this experiment were detected 24h after this surgery. First of all, we record of neurological score, measure the infarct volume ratio and observe HE staining of ischemic brain tissue. Then, the interventional effects of OMT on oxidative stress of cerebral ischemic rats was investigated by measuring the vitality of SOD, CAT and GSH-Px and the content of MDA in peripheral serum. And then, the interventional effects of OMT on the endoplasmic reticulum stress pathway and the endoplasmic reticulum stress-induced apoptosis pathway were investigated by measuring the expression of GRP78, XBP1, ATF6, CHOP and Caspase-12 and the activity of Caspase-12 in ischemic brain tissue.Results: 1. Preventive administration of OMT could improve neurological function, reduce the infarct volume ratio, maintain the morphological characteristics of ischemic brain tissue and alleviate the damage of tissue with a certain degree of dose-effect relationship. The results revealed that OMT could intervene the cerebral ischemic injury.2. Preventive administration of OMT could enhance the vitality of SOD, CAT and GSH-Px and reduce the content of MDA with a certain degree of dose-effect relationship. The results revealed that OMT could intervene the oxidative stress response of cerebral ischemia of rats.3. Preventive administration of OMT could suppress the expression of GRP78, XBP1, ATF6, CHOP and Caspase-12 and the activity of Caspase-12 with a certain degree of dose-effect relationship. The results revealed that OMT could intervene the endoplasmic reticulum stress pathway and the endoplasmic reticulum stress-induced apoptosis pathway.Conclusion:Preventive administration of OMT could intervene the focal cerebral ischemic injury. Its mechanism includes at least two aspects. For one thing, targeting oxidative stress response, OMT can suppress the creation of free radicals, so it can intervene the cerebral ischemic injury; For the other thing, targeting endoplasmic reticulum stress and endoplasmic reticulum stress-induced apoptosis, OMT can suppress the expression of marker proteins in the endoplasmic reticulum stress pathway and the endoplasmic reticulum stress-induced apoptosis pathway, so it can intervene the cerebral ischemic injury.
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