| Background and objectiveIschemic stroke is a serious disease which threat to human health and is the second killer after tumor. It has the characteristics of high incidence and high morbidity and high moratality, and wins widespread concern. For the treatment of ischemia stroke, thrombolytic therapy may improve the blood circulation of the ischemia area. The drugs to promote nerve repair and functional recontruction were confirmed in animal experiments, but not be confirmed in clinical application. Thus, the dilemma of experimental success and practical failure encourages the search for new applications of already-approved drugs.Hypoxia-inducible factor-1α (HIF-1α) is an important transcription factor, which is extremely sensitive to low oxygen environment. It participates in the process of oxygen pathophysiological events of the brain ischemia, and plays a protective effect on ischemic brain tissue through a variety of mechanisms. In recent years, many experimental research shows that HIF combines with HRE (hypoxic response element) under hypoxia, then cause the transcription of downstream target genes, VEGF, EPO for example. The transcriptional activations mainly regulate anaerobic metabolism, promote vascular proliferation, improve nerve cell tolerance to ischemia and hypoxia, so as to reduce the brain tissue damage.Bezafibrate, a peroxisome proliferator-activated receptor-α (PPARα) agonist, has been used in clinical for a long time as lipid-lowering drug. Animal experiments show that Bezafibrate has a protective effect on various organs of the body (such as liver, kidney, intestines, etc.) suffering from ischemia and reperfusion injury, but it is rarely reported about cerebral ischemia reperfusion injury and the specific mechanism is onclear.In this study, we use a suture method to produce ischemia-reperfusion injury model, then to observe the rat neural function defect, cerebral infarct size, hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) expression, and investigate the protective effect of Bezafibrate on brain injury induced by global cerebral ischemia/reperfusion.Materials and Methods90adult male SD rats were subjected to middle cerebral artery occlusion90min and followed reperfusion by suture method. The experimental groups included sham group, ischemia-reperfusion group, bezafibrate treatment group, each group divided into ischemia and reperfusion6h,12h,24h, three time points. The sham group:only exposure and separate the common carotid, internal carotid and external carotid artery, not intravascular obstruction. The ischemia-reperfusion group:MCAO/R model rat were given injected intraperitioneal injection of dimethyl sulfoxide (DMSO) as the same volume of bezafibrate treatment group. The bezafibrate treatment group: MCAO/R model rat were given intraperitioneal injection bezafibrate (6mg/kg)30min before ischemia occurred. The ischemia-reperfusion rats were observed at6h,12h and24h after ischemia. We judge MCAO/R model making success through evaluation of various neurological score, brain tissue slices were stained with HE, the morphological characteristics of cells in the ischemic region and around under light microscope and2%triphenylterazolium chloride(TTC). The expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) were determined by immunohistochemistry.Results 1Cerebral ischemia and reperfusion model:Cerebral ischemia and reperusion model of rat contralateral limb paralysis. The infarct area could not be stained by TTC, and got ischemic pathological changes, which confirmed the cerebral ischemia and reperfusion model successful.2Neurological score:The ischemia-reperfusion group and bezafibrate treatment group all appear different degrees of neurobehavioral function defect. The neurological score of ischemia-reperfusion group at different time points was3.10±0.99,2.30±0.95,2.10±0.99, and with the extension of time neural function resumed. The neurological score of bezafibrate treatment group was2.40±0.84、1.60±0.97、1.40±0.70. Benzafibrate significantly ameliorated neurobehavioral scores after cerebral ischemia reperfusion (P<0.05).3immunohistochemisty for HIF-la:After the ischemia-reperfusion, the expression of HIF-la increases significantly in the adult mouse brain, and reached the peak at the12h,and then gradually decreased. The HIF-1α expression of bezafibrate treatment group was higher than the ischemia-reperfusion group (P<0.05).4immunohistochemisty for VEGF:After ischemia-reperfusion, VEGF could be mainly seen around Ischemia area in infarct side, and also be seen in neurons, gliacyte, and kytoplasm of vascular endothelial cell. In the brain tissue of the sham operation group, the expression of VEGF was weakly. After ischemia and reperfusion, it increased obviously and reached the hightest at the12h, and then gradually decreased. The VEGF expression of bezafibrate treatment group was higher than the ischemia-reperfusion group (P<0.05).ConclusionsBezafibrate plays a neuroprotective effect on cerebral ischemia reperfusion injury by improving the neurological deficit, and its mechanism may be relate to increase HIF-1alpha, VEGF expression, improve brain tissue hypoxia tolerance for ischemia, protect the nerve of cerebral ischemia reperfusion. This study provides the experimental basis for clinical treatment of ischemic cerebrovascular disease. |
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