Manganese neurotoxicity: a mechanistic hypothesis.
This review provides a summary of the presentations and abstracts presented at the 15th International Neurotoxicology Conference which may contribute 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 (1) the factors controlling Mn2+ uptake and distribution within the CNS, (2) account for the apparent selectivity of dopaminergic neurons, (3) analyze the role of mitochondrial dysfunction and (4) provide data to support or refute the role of oxidative injury 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 transport and the role of Mn2+ as a pro-oxidative toxicant in conjunction with changes in iron concentration. Within the synaptic milieu, Mn(2+)-mitochondrial interaction will influence mitochondrial--Ca2+ transport kinetics leading to defective mitochondrial function, decreased oxidative phosphorylation, decreased ATP and accumulation of reactive oxygen species. Under the influence of excessive depolarization, energy failure will occur leading to secondary activation of an excitotoxic state. These conceptual ideas provide for mechanistic based hypotheses and testing and are likely to lead to rational therapeutic avenues directed against Mn2+ neurotoxicity.
Verity
M A
MA
Department of Pathology and Laboratory Medicine, UCLA Medical Center 90095-1732, USA. averity@pathology.medsch.ucla.edu
D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000494:pharmacology; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000493:pharmacokinetics; D008345:Manganese / Q000493:pharmacokinetics; D020149:Manganese Poisoning; D008928:Mitochondria / Q000187:drug effects*; D009422:Nervous System Diseases / Q000139:chemically induced*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects*
D018492:Dopamine Antagonists; D008345:Manganese; D007501:Iron; D002118:Calcium