Elucidation of endogenous protective factors regulating neuronal death in neurodegenerative disorders.

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This study was aimed to elucidate the protective action of endogenous factors regulating neuronal death induced by glutamate and reactive oxygen species (ROS). We carried out three protects by using in vitro primary cultures.1) We elucidated the chemical structure of non-protein neuroprotective substance isolated from the ether extract of fetal calf serum. NMR analysis revealed the structure of the compound being hydroxy- 17-methylsufinylatisan-19-oic acid. This compound was a novel atisane-type diterpenoid. The compound was named "serofendic acid" as it was isolated from serum and possessed potent neuroprotective activity.2) The role neuronal activity in the survival of dopaminergic neurons was investigated by using slice cultures of the rat mesencephalon. The study with glutamate receptor antagonists suggested that calcium influx induced by depolarization under moderate and persistent stimulation of glutamate receptors accelerates neuronal survival and that CAMP plays an important role in the neurotrophic effect of glutamate receptor-mediated calcium influx.3) We examined the neuroprotective effects of endogenous substances including vitamin D, estradiol and neurotrophins. Those substances inhibited glutamate neurotoxicity in a concentration dependent manner. They also inhibited neurotoxicity induced by calcium ionophore and ROS. Intracellular ROS generation was also prevented by the pretreatment of those substances. These results suggest that vitamin D, estradiol and neurotrophins elicit protective actions against glutamate neurotoxicity to promote neuronal survival by reducing radical stress during the process of neurodegenerative disorders.