Endogenous factors regulating neuronal apoptosis

Apoptosis and necrosis of neurons induced by glutamate and nitric oxide (NO) are associated with various disorders including hypoxic-ischemic brain injury, Alzheimer's disease and Parkinson's disease. In search of endogenous protective factors that inhibit NO-mediated glutamate neurotoxicity, we found that excitotoxicity is suppressed by certain neurotransmitters such as nicotinic acetylcholine and dopamine and growth factors such as NGF and BDNF. We recently purified and isolated a novel neuroprotective substance, which has been named 'serofendic acid', from a lipophilic fraction of fetal calf serum. Mass spectrometry and NMR spectroscopy revealed the chemical structure of serofendic acid (15-hydroxy-17-methylsulfinylatisan-19-oic acid) as a sulfur-containing atisane-type diterpenoid. Serofendic acid exhibited potent protective actions on cortical neurons against neurotoxicity of a NO donor as well as of glutamate, although it did not show appreciable influences on glutamate receptor-mediated responses in these neurons. Electron spin resonance analysis demonstrated that serofendic acid had no direct scavenging activity on NO radicals but was capable of inhibiting the generation of hydroxyl radicals. These findings suggest that serofendic acid is a low-molecular-weight bioactive factor that promotes survival of CNS neurons, probably through the attenuation of free radical-mediated insults.