Manganese neurotoxicity: A mechanistic hypothesis

This review provides a summary of the presentations and abstracts presented at the 15(th) International Neurotoxicology Conference which may contribut e to an understanding of the mechanism and pathogenesis of manganese (Mn2+) neurotoxicity. We propose that an understanding of the pathogenesis of Mn2 + neurotoxicity must incorporate data on (I) the factors controlling Mn2+ u ptake and distribution within the CNS, (2) account for the apparent selecti vity of dopaminergic neurons, (3) analyze the role of mitochondrial dysfunc tion and (4) provide da ta to support or refute the role of oxidative injur y in the genesis of toxicity. We propose a multifactor hypothesis coupling Mn2+ uptake with coincident transport of aluminum and iron. Selectivity of dopaminergic neurons is dependent upon interactions of Mn2+ with dopamine t ransport and the role of Mn2+ as a pro-oxidative toxicant in conjunction wi th changes in iron concentration. Within the synaptic milieu, Mn2+-mitochon drial interaction will influence mitochondrial - Ca2+ transport kinetics le ading to defective mitochondrial function, decreased oxidative phosphorylat ion, decreased ATP and accumulation of reactive oxygen species. Under the i nfluence of excessive depolarization, energy failure will occur leading to secondary activation of an excitotoxic state. These conceptual ideas provid e for mechanistic based hypotheses and testing and are likely to lead to ra tional therapeutic avenues directed against Mn2+ neurotoxicity. (C) 1999 In ter Press, Inc.