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Vol. 302, Issue 1, 26-35, July 2002

Oxidative Stress and Mitochondrial-Mediated Apoptosis in Dopaminergic Cells Exposed to Methylcyclopentadienyl Manganese Tricarbonyl

Masashi Kitazawa, Jarrad R. Wagner1, Michael L. Kirby, Vellareddy Anantharam and Anumantha G. Kanthasamy

Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, Iowa

Methylcyclopentadienyl manganese tricarbonyl (MMT), an organic manganese-containing gasoline additive, was investigated to determine whether MMT potentially causes dopaminergic neurotoxic effects. MMT is acutely cytotoxic and dopamine-producing cells (PC-12) seemed to be more susceptible to cytotoxic effects than nondopaminergic cells (striatal gamma -aminobutyric acidergic and cerebellar granule cells). MMT also potently depleted dopamine apparently by cytoplasmic vesicular release to the cytosol, a neurochemical change resembling other dopaminergic neurotoxicants. Generation of reactive oxygen species (ROS), an early effect in toxicant-induced apoptosis, occurred within 15 min of MMT exposure. MMT caused a loss of mitochondrial transmembrane potential (Delta Psi m), a likely source of ROS generation. The ROS signal further activated caspase-3, an important effector caspase, which could be inhibited by antioxidants (Trolox or N-acetyl cysteine). Predepletion of dopamine by using alpha -methyl-p-tyrosine (tyrosine hydroxylase inhibitor) treatment partially prevented caspase-3 activation, denoting a significant dopamine and/or dopamine by-product contribution to initiation of apoptosis. Genomic DNA fragmentation, a terminal hallmark of apoptosis, was induced concentration dependently by MMT but completely prevented by pretreatment with Trolox, deprenyl (monoamine oxidase-B inhibitor), and alpha -methyl-p-tyrosine. A final set of critical experiments was performed to verify the pharmacological studies using a stable Bcl-2-overexpressing PC-12 cell line. Bcl-2-overexpressing cells were significantly refractory to MMT-induced ROS generation, caspase-3 activation, and loss of Delta Psi m and were completely resistant to MMT-induced DNA fragmentation. Taken together, the results presented herein demonstrate that oxidative stress plays an important role in mitochondrial-mediated apoptotic cell death in cultured dopamine-producing cells after exposure to MMT.

1 Present Address: Department of Chemistry, California State University, 2555 E. San Ramon Ave., Fresno CA 93740.

0022-3565/02/3021-0026$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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