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The Journal of Neuroscience, April 1, 2002, 22(7):2637-2649

Caspase Inhibitors Attenuate 1-Methyl-4-Phenylpyridinium Toxicity in Primary Cultures of Mesencephalic Dopaminergic Neurons

James Bilsland¹, Sophie Roy², Steve Xanthoudakis², Donald W. Nicholson², Yongxin Han², Erich Grimm², Franz Hefti¹, and Sarah J. Harper¹

¹ Merck, Sharp and Dohme Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, United Kingdom, and ² Merck-Frosst Centre for Therapeutic Research, Pointe Claire-Duval, Quebec, H9R 4P8, Canada

Parkinson's disease is characterized by a loss of dopaminergic nigrostriatal neurons. This neuronal loss is mimicked by the neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺). MPP⁺ toxicity is mediated through inhibition of mitochondrial complex I, decreasing ATP production, and upregulation of oxygen radicals. There is evidence that the cell death induced by MPP⁺ is apoptotic and that inhibition of caspases may be neuroprotective. In primary cultures of rat mesencephalic dopaminergic neurons, MPP⁺ treatment decreased the number of surviving dopaminergic neurons in the cultures and the ability of the neurons to take up [³H]dopamine ([³H]DA). Caspase inhibition using the broad-spectrum inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) spared MPP⁺-treated dopaminergic neurons and increased somatic size. There was a partial restoration of neurite length in zVAD-fmk-treated cultures, but little restoration of [³H]DA uptake. Peptide inhibitors of caspases 2, 3, and 9, but not of caspase 1, caused significant neuroprotection. Two novel caspase inhibitors were tested for neuroprotection, a broad spectrum inhibitor and a selective caspase 3 inhibitor; both inhibitors increased survival to >90% of control. No neuroprotection was observed with an inactive control compound. MPP⁺ treatment caused chromatin condensation in dopaminergic neurons and increased expression of activated caspase 3. Inhibition of caspases with either zVAD-fmk or a selective caspase 3 inhibitor decreased the number of apoptotic profiles, but not expression of the active caspase. We conclude that MPP⁺ toxicity in primary dopaminergic neurons involves activation of a pathway terminating in caspase 3 activation, but that other mechanisms may underlie the neurite loss.

Key words: Parkinson's disease; apoptosis; MPP⁺; caspase; neuroprotection; dopaminergic neurons

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2272637-13$05.00/0

This article has been cited by other articles:

				B. S. Han, H.-S. Hong, W.-S. Choi, G. J. Markelonis, T. H. Oh, and Y. J. Oh Caspase-Dependent and -Independent Cell Death Pathways in Primary Cultures of Mesencephalic Dopaminergic Neurons after Neurotoxin Treatment J. Neurosci., June 15, 2003; 23(12): 5069 - 5078. [Abstract] [Full Text] [PDF]

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