| ObjectiveHypoxic-ischemic encephalopathy (HIE) can cause neuronal death and apoptosis in neonatal brain. It not only endangers neonatal life, but also leads to neurological disabilities. One of the main pathogeneses of HIE is early necrosis and delayed apoptosis of neurons followed by energetic depletion induced by oxygen and glucose deprivation. In this course, overactivation of glutamate receptors, especially N-methyl-D-aspartate (NMDA) receptors, can lead to a massive influx of sodium and calcium which triggers a biochemical cascade, and ends up with neuronal necrosis and apoptosis. Memantine, a safe non-competitive NMDA receptor blocker, can provide neuroprotection without impairing normal brain functioning. Topiramate is an AMPA/KA receptor blocker and use-dependent sodium channel blocker with several other neuroprotective actions. Based on studies about glutamate receptor family, the two neuroprotectants may have interdependent and synergistic function. According to the previous studies, we hypothesized that the administration of memantine combined with topiramate would be effective to attenuate hypoxic-ischemic brain injury (HIBI) in neonatal rats.Materials and MethodsSeven-day-old Sprague-Dawley rat pups were subjected to ligation of right common carotid artery followed by hypoxia for 2 hours according to Rice's method, and then were randomly and double-blindly assigned to one of four groups: vehicle(saline), memantine( 20mg/kg loading dose i.p. followed by 1mg/kg maintenance dose every 12h for 4 times), topiramate(40mg/kg loading dose i.p. , followed by 10mg/kg maintenance dose every 12h for 4 times) and combination group( both memantine and topiramate at same doses and schedule).The cellular apoptotic neurodegeneration was assessed by TUNEL staining and caspase-3 immunohistochemical staining at 48h after HI. Acute neuronal injury was evaluated by microscopic damage grading at 72h after HI. The foot fault test was performed to assess the neurofunction at 21d after HI. Brain injury was evaluated by gross damage and weight deficit of the right hemisphere which was presented as the percentage of hemispheric weight loss of the right side relative to the left at 22d after HI. Data are presented as mean±S.D. Comparisons were performed by one-way ANOVA with Fisher's post hoc test by using SPSS 15 for windows. Differences were considered significant when p<0.05.Results1. Positive cell counting of TUNEL staining and caspase-3: In the CA1 sector of the hippocampus and subcortical white matter, the numbers of apoptotic cells in the combination group were significantly reduced compared with the vehicle group. The result of caspase-3 positive cell counting is consistent with that of TUNEL staining.2. Microscopic damage grading: The histopathologic score in the combination group were significantly lower compared with the vehicle group in the cortex, hippocampus and thalamus.3. Foot fault test: The number of foot-faults per pup was significantly less in the combination group than that in the vehicle group.4. Gross brain damage grading: The neurologic damage score was significantly lower in the combination-treated group than that in the vehicle-treated group.5. Wight deficit of the right hemisphere: The weight deficit of the right hemisphere in the combination group was significantly reduced compared with the vehicle group.Conclusion1. The combination of memantine and topiramate not only attenuates acute neural injury but also reduces brain injury in a long period.2. The combination of memantine and topiramate can reduce cellular apoptosis in the CA1 sector of the hippocampus and subcortical white matter.3. The combination of memantine and topiramate improved both pathological outcome and neurofunctional performance significantly.
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