Excitotoxins, aging, and environmental neurotoxins: implications for understanding human neurodegenerative diseases

We are an aging society and current demographic trends point to a likely increase in age-related neurodegenerative diseases. The aged population may have a number of unique risk factors that result in a predisposition to neuronal damage from environmental neurotoxins. This symposium addressed the involvement of excitatory amino acids as final common mediators of neuronal death associated with various types of neurotoxic insult. The roles of oxidative stress, mitochondrial energy metabolism, and disruption of calcium homeostasis were discussed in relation to excitoxicity and several experimental models of human neurodegenerative diseases. The neurotoxic actions of kainic acid, 3-nitropropionic acid, cyanide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and methamphetamine were examined for their relevance as models of human neurodegenerative disorders. The mechanisms of action of excitotoxins in experimental models of Huntingtons's disease and Parkinson's disease were explored in light of the enhanced susceptibility and potential vulnerability of the aged nervous system to neurotoxins that perturb cellular metabolism and homeostatic processes. Bioenergetic defects and oxidative stress were found to be critical links in a neurotoxic cascade of events that trigger the sustained release of excitotoxic amino acids. The interrelationships among the aging process, the pathophysiology of neurodegenerative diseases, and the mechanism of action of various neurotoxins were addressed from the unifying perspective of the excitotoxic hypothesis of neuronal death.