Mechanisms of protectiion by neurotrophins against NO-mediated glutamate neurotoxicity

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This project is aimed to determine the mechanisms of protective action of neurotrophins against glutamate neurotoxicity in the cerebral cortex by using cortical cultures derived from fetal rats. Brain-derived neurotrophic factor (BDNF) potently prevented NMDA receptor-mediated glutamate neurotoxicity when the cultures were exposed to BDNF for 24 hr prior to glutamate exposure. Protective effect of BDNF was inhibited by an inhibitor of protein synthesis. Those results suggest that de novo synthesis of intracellular proteins is involved in the neuroprotective action of BDNF.BDNF induced tyrosine phosphorylation of its high affinity receptor, TrkB.By contrast, the effect of BDNF was not affected by the addition of antibody for p75, a low affinity neurotrophin receptor. BDNF did not increase ceramide formation. BDNF prevented cytotoxicity induced by a calcium ionophore such as ionomycin and a NO donor such as S-nitrosocysteine. Those findings indicate that BDNF selectively interacts with TrkB to promote de novo synthesis of functional molecules which ameliorate neurotoxicity triggered by free radicals including nitric oxide and superoxide. The results of our project give a new scope for the creation of novel drugs protecting neuronal death in neurodegenerative disorders.