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The Journal of Neuroscience, February 15, 1999, 19(4):1284-1293
Distinct Mechanisms Underlie Neurotoxin-Mediated Cell Death in Cultured Dopaminergic Neurons
Julie Lotharius1, Laura L. Dugan2, and Karen L. O'Malley1 1 Department of Anatomy and Neurobiology and 2 Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110
Oxidative stress is thought to contribute to dopaminergic cell death in Parkinson's disease (PD). The neurotoxin 6-hydroxydopamine (6-OHDA), which is easily oxidized to reactive oxygen species (ROS), appears to induce neuronal death by a free radical-mediated mechanism, whereas the involvement of free radicals in N-methyl-4-phenylpyridinium (MPP+) toxicity is less clear. Using free radical-sensitive fluorophores and vital dyes with post hoc identification of tyrosine hydroxylase-positive neurons, we monitored markers of apoptosis and the production of ROS in dopaminergic neurons treated with either 6-OHDA or MPP+. Annexin-V staining suggested that 6-OHDA but not MPP+-mediated cell death was apoptotic. In accordance with this assignment, the general caspase inhibitor Boc-(Asp)-fluoromethylketone only blocked 6-OHDA neurotoxicity. Both toxins exhibited an early, sustained rise in ROS, although only 6-OHDA induced a collapse in mitochondrial membrane potential temporally related to the increase in ROS. Recently, derivatives of buckminsterfullerene (C60) molecules have been shown to act as potent antioxidants in several models of oxidative stress (). Significant, dose-dependent levels of protection were also seen in these in vitro models of PD using the C3 carboxyfullerene derivative. Specifically, C3 was fully protective in the 6-OHDA paradigm, whereas it only partially rescued dopaminergic neurons from MPP+-induced cell death. In either model, it was more effective than glial-derived neurotrophic factor. These data suggest that cell death in response to 6-OHDA and MPP+ may progress through different mechanisms, which can be partially or entirely saved by carboxyfullerenes.
Key words: dihydrorhodamine; dihydroethidium; rhodamine 123; neuroprotection; MPTP; mesencephalic
Copyright © 1999 Society for Neuroscience 0270-6474/99/1941284-10$05.00/0
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