EXCITOTOXINS, AGING, AND ENVIRONMENTAL NEUROTOXINS - IMPLICATIONS FORUNDERSTANDING HUMAN NEURODEGENERATIVE DISEASES

We are an aging society and current demographic trends point to a like ly increase in age-related neurodegenerative diseases. The aged popula tion may have a number of unique risk factors that result in a predisp osition to neuronal damage from environmental neurotoxins. This sympos ium addressed the involvement of excitatory amino acids as final commo n mediators of neuronal death associated with various types of neuroto xic insult. The roles of oxidative stress, mitochondrial energy metabo lism, and disruption of calcium homeostasis were discussed in relation to excitoxicity and several experimental models of human neurodegener ative diseases. The neurotoxic actions of kainic acid, 3-nitropropioni c acid, cyanide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and met hamphetamine were examined for their relevance as models of human neur odegenerative disorders. The mechanisms of action of excitotoxins in e xperimental models of Huntingtons's disease and Parkinson's disease we re explored in light of the enhanced susceptibility and potential vuln erability of the aged nervous system to neurotoxins that perturb cellu lar metabolism and homeostatic processes. Bioenergetic defects and oxi dative stress were found to be critical links in a neurotoxic cascade of events that trigger the sustained release of excitotoxic amino acid s. 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 excit otoxic hypothesis of neuronal death. (C) 1995 Academic Press. Inc.