Characterization of Neurotoxic Effects of NMDA and the Novel Neuroprotection by Phytopolyphenols in Mice

Excitotoxicity plays a major role in various neurological disorders. In this study, we explored the behavioral and neurotoxic effects of intraventricular NMDA administration in mice. After NMDA injection, acute seizures were followed by impairments in locomotor activity, motor performance on a rotarod, and climbing ability. Mice killed 1 day after NMDA administration showed increased synaptosomal reactive oxygen species ROS production and calcium concentration and decreased mitochondrial membrane potential, mitochondrial reductase activities, and neuronal membrane Na(+), K(+)-ATPase and mg(2+)-ATPase activities. One and 3 days after excitotoxic injury, Golgi stains showed that dendritic length and spine density were significantly decreased in neurons of the hippocampal dentate gyms. Some mice received honokiol, tea polyphenol plus memantine, and honokiol plus memantine prior to NMDA treatment; the occurrence of generalized seizures was attenuated, seizure scores were reduced, latency to generalized seizures was prolonged, and motor impairments were lessened. Moreover, all of the neurochemical changes of the synaptosomes were also ameliorated. In conclusion, the behavioral and neurotoxic effects of intracerebroventricular injection of NMDA were ameliorated by treatment with honokiol alone or combined treatment with either tea polyphenol plus memantine or honokiol plus memantine, but only partly by either tea polyphenol or memantine alone. The therapeutic potential of these neuroprotective regimens in treating excitotoxicity-related diseases merits for further investigation.