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| Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons |
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| Author(s): Lotharius J, Dugan LL, O'Malley KL |
| Source: JOURNAL OF NEUROSCIENCE Volume: 19 Issue: 4 Pages: 1284-1293 Published: FEB 15 1999 |
| Times Cited: 218 References: 42 |
| Abstract: Oxidative stress is thought to contribute to dopaminergic cell death in Parkinson's disease (PD). The neurotoxin B-hydroxydopamine (6-OHDA), which is easily oxidized to reactive oxy gen 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 (C-60) molecules have been shown to act as potent antioxidants in several models of oxidative stress (Dugan et al., 1997), Significant, dose-dependent levels of protection were also seen in these in vitro models of PD using the C-3 carboxyfullerene derivative. Specifically, C-3 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Lotharius, J (reprint author), Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA |
Addresses:
1. Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA
2. Washington Univ, Sch Med, Ctr Study Nervous Syst Injury, St Louis, MO 63110 USA |
| Publisher: SOC NEUROSCIENCE, 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA |
| Subject Category: Neurosciences |
| IDS Number: 166XP |
| ISSN: 0270-6474 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |