Protective mechanisms of endogenous bioactive molecules on neuronal death associated with neurodegenerative disorders

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We focused on endogenous low-molecular-weight substances as intrinsic protective mechanisms of the brain against glutamate-induced neuronal death. (1)Serofendic acid, a novel substance identified from fetal calf serum, markedly attenuated glutamate neurotoxicity. Serofendic acid inhibited NO donor-induced neuronal death, but did not affect glutamate receptor-mediated current responses. Serofendic acid also prevented generation of hydroxyl radical, and inhibited neuronal death induced by paraquat and hydrogen peroxide. Dimethylsulfoxide, a structural unit contained in serofendic acid, exhibited similar effects, but the effective concentrations of dimethylsulfoxide were about 3000 times as high as those of serofendic acid, suggesting that serofendic acid possesses neuroprotective actions independent of radical-scavenging activity. (2)We tested neuroprotective effects of several neurosteroids, as endogenous substances whose physicochemical properties resemble those of serofendic acid. Pregnenolone sulfate exacerbated, whereas pregnanolone sulfate inhibited, NMDA neurotoxicity. These effects were attributable to direct modulation of NMDA receptor channels by these compounds. (3)We examined neuroprotective activities of vitamin E analogs. Tocotrienols provided a significant protective effect against hydrogen-peroxide induced neuronal death, whereas α-tocopherol was without effect. Tocotrienols also inhibited induction of neuronal death by superoxide, NO as well as depletion of glutathione. Staurosporine-induced cell death was inhibited by α-tocotrienol. Several members of vitamin E analogs were shown to block apoptosis by mechanims independent of their antioxidant actions. (4)We found that acetylcholinesterase inhibitors including donepezil markedly inhibited glutamate neurotoxicity. The neuroprotective action emerged after prolonged treatment of neurons with donepezil for at least 24 h, and was mediated by stimulation of nicotinic acetylcholine receptors.