The Experimental Study On Topiramate Protective Effect In Focal Cerebral Ischemic Reperfusion Rat Models

Background and objective:Topiramate (topamax) is a sultate monosaccharid compound, structurally-novel anticonvulsant. The antiepileptic action mechanisms of topiramate have beenidentified basically, including: a negative modulatory effect on voltage-activated neuronal Na+ channels; a negative modulatory effect on Kaiante/AMPA-recep tors and a positive modulatory effect on some GABA receptors. More and more external researches have been proved that Topiramate doesnot only have an antiepileptic action, but a protective effect to cerebral ischemic damage. Now few report which study on Topiramate protective effect of cerebral ischemic da mage and mechanisms has been carried out domestically. In this study, the protective effect of Topiramate to cerebral ischemic reperfusion damage in rat models and action mechanisms were investigated at the level of cellular and molecular. So as to explore a new therapeutic measure of cerebral infarction and toprovide experimental foundations for prevention and treatment of the brain infarction. Method:40 adult Wistar rats were randomly divided into 5 groups, including normal group, sham-operation group, ischemic group, large dose-treat group and sma 11 dose-treat group. The focal cerebral ischemic model was made by occluding middle cerebral artery (MCA) for 2 hours and reperfusing for 72 hours. The rats of the treatable groups were given either large dose (100mg/kg) or small d ose (50mg/kg) topiramate during the ischemia and the reperfusion and 3 days after that. The rats of the sham-operation group were accordingly given normalsaline of the same dose. All the rats were killed to collect the brain in 72 hours after the neural function value analysis were done. The brain tissues wereused for the observation of apoptosis of the neurocytes by using TUNEL staining and the expression of NSE, and the data were calculated by image analysis system. Results:In the ischemic group, the number of neurocytes reduced obviously, with many of them ended in apoptosis. The cell nucleus of the neurocyte atrophied,which is the characters of the apoptosis. In the topiramate treated groups. Similar changes could also been seen , but much less than that is in the ischemicgroup. These changes were less in the large dose group compared to the small dose group too.Apoptosis results of TUNEL staining: TUNEL staining showed no apoptosis cells were seen in the normal group, and these were also scattered in the br ain of rats in the sham-operation group. However, TUNEL-positive cells were noted in the ischemic group and both the topiramate-treated groups. We may see deep brown staining in the nucleus of the hippocampus and cortical neurons.Topiramate-treated groups resulted in significantly fewer TUNEL-positive cellsin the neurons compared with ischemic group (p<0.01); and the TUNEL-positive cells decreased remarkablely in large-dose group compared with the small-dose group (P<0.05).The expression of NSE in topiramate treatment group increased than the fame-operation group in 72th hour after reperfusion(P<0.01). In treatment group, the score of the neurologic grade of the large-dose group increased(P<0.05), the expression of NSE protein increased remarkablely in cerebral tissue(P<0.05) compared with the small-dose group. Neuronal function value analysis: either the large dose of topiramate-treated group or the small dose of topiramate-treated group compare with the ischemic reperfusion without any treatment has statistical difference (p<0.01). the differences between the two treated groups are statistical too (p<0.05). Conclusions:1. Topiramate has a neuro-protective effect against neuronal damage followingfocal ischemic in the Wistar rats.2. One of the neuro-protective mechanisms of topiramate is that it can reducethe apoptosis after the ischemia and the reperfusion in the focal models of Wistar rats.3. Another one of the neuro-protective mechanisms of Topiramate is that Topiramate could increasing the expression of NSE in brain tissue.4. Topiramate reduced neuronal damage induced by focal ischemic of Wistarrats in a dose-dependent manner, large dose of topiramate (100mg/kg) administration could significantly suppressed these neuronal cell damages.