| With the insight into cerebral ischemia mechanisms it is found that simply interrupting one step of the pathological cascade that occurs during the ischemic process does not cause effective neuroprotection and thrombolysis is still the major therapeutic means clinically for acute stoke treatment. But reperfusion after thrombolysis may aggravate cerebral injury. Thus it is urgent to study and develop effective neuroprotectors against reperfusion injury.Dipfluzine (Dip), a new diphenylpiperazine calcium channel antagonist, was first developed by Pharmaceutical School of Hebei Medical University. Dipfluzine showed neuroprotection in the global cerebral ischemia model by selectively cerebral vasodilation, attenuating cerebral blood flow decrease in ischemic region, relieving cerebral edema, and inhibiting the increasing of extracellular excitatory amino acid (EAA). In present study the changes of cerebral blood flow, apoptosis, intracellular calcium concentration, injury from free radicals and the changes of some important amino acids relevant to cerebral ischemia were taken to evaluate the neuroprotective effects and mechanisms of dipfluzine on the focal cerebral ischemia and reperfusion injury induced by endothelin-1(ET-1) in rats.Part 1 The focal cerebral ischemia and reperfusion modelinduced by endothelin-1Objective: To establish an endothelin-1-induced focal cerebral ischemia and reperfusion model and find a proper endothelin-1 (ET-1) concentration which was suitable for investigating the pathophysiological mechanism of cerebral ischemia-reperfusion and screening neuroprotectors. Methods: 40 Wistar rats were randomly divided into 5 groups, sham group, ET-1300pmol group, ET-1360pmol group, ET-1400pmol group and ET-1500pmol group. The focal cerebral ischemia-reperfusion model was established by infusing ET-1 near the middle cerebral artery. The rats in sham operation group underwent the same surgical procedure with infusing artificial cerebral spinal fluid to the proximity of MCA. The changes of cerebral blood flow (CBF) in striatum were monitored using hydrogen clearance technique and the mean arterial blood pressure (MABP) were measured by intubation of caudal artery. The neurological scores were performed at 6h after ET-1 infusion and the cerebral infarct volume was identified by TTC staining at 24h after ET-1 application.Results: ET-1 induced a dose-dependent reduction of cerebral blood flow in striatum and the cerebral blood flows at 10min after ET-1 infusion were the lowerest . They were (27.1±2.9)% in group 300pmol, (12.7±2.1%) in group 360pmol, (11.9±1.8)% in group 400pmol and (9.5±1.6)% in group 500pmol , respectively. Neurological score showed that infusing different concentration of ET-1 near the middle cerebral artery could induce variable grade neurological deficit, which were 2.8±0.5 in group 300pmol, 6.1±0.6 in group360 pmol, 6.9±0.4 in group 400pmol and 9.3±0.5 in group 500pmol, respectively (P<0.01, compared with sham group). The rats in sham group showed no neurological deficit. The infarct volumes were increased with the increment of ET-1 concentration and showed a close correlation, which were (3.9±0.3)% in group 300pmol, (7.4±0.5)% in group 360pmol, (11.3±1.3)% in group 400pmol, and (16.2±1.8)% in group 500pmol respectively , r = 0.9926 (P<0.05). Endothelin-1 infusion did not affect the mean arterial blood pressure (MABP) in rats.Conclusion: The 400pmol of ET-1 was the suitable concentration for establishing a relatively ideal animal model of focal cerebral ischemia and reperfusion, which is simple, good reproducible and similar to the condition in human stroke, and could be used for investigating the pathophysiological mechanism of cerebral ischemic-reperfusion and screening neuroprotectors. Part 2 Protective effects of dipfluzine on focal cerebral ischemia and reperfusion injury and the intracellular calcium concentrationObjective: To evaluate the neuroprotective effects of dipfluzine (Dip) and flunarizine(Flu) on focal cerebral ischemia-reper...
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