Pharmacological study on neurogenesis enhancing factors expressed by neuronal death

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Throughout history, the activation of N-methyl-D-asparate (NMDA) receptors has been well known to induce neuronal cell death in vivo and in vitro. In addition to this role, we showed that NMDA receptors have the protective role against excitotoxic injury induced by kainic acid in mouse hippocampus in vivo. Recent studies have shown that NMDA receptor modulates neurogenesis in dentate gyrus of hippocampus. To elucidate roles of NMDA signals, we investigated the involvement of NMDA receptors in degeneration and regeneration of neurons. Treatment with NMDA antagonists (MK-801, SM31900 or ifenprodil) significantly suppressed TMT-induced enhancement of BrdU incorporation in the dentate subgranular zone of mice. Nerual progenitor cells from embryonic mouse hippocampus were cultured in DMEM/F12 medium containing growth factors for assessment of cell proliferation in either the presence or absence of these antagonists. Treatment with any of these antagonists led to a decrease in the number and the size of surviving neurospheres. Western blotting analysis by using anti-α-fodrin antibody showed that treatment with SM31900 produces a significant reduction in a 150 kD product cleaved by calpain. Calpain inhibitors markedly decreased the neurosphere formation in cultured neural progenitor cells. These results suggest that NMDA signals would play positive roles in survival and regeneration of neurons.