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The Journal of Neuroscience, October 15, 1998, 18(20):8145-8152

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride Neurotoxicity Is Attenuated in Mice Overexpressing Bcl-2

Lichuan Yang1, 3, Russell T. Matthews1, 3, Jörg B. Schulz4, Thomas Klockgether4, Andrew W. Liao2, Jean-Claude Martinou5, John B. Penney Jr.3, Bradley T. Hyman2, and M. Flint Beal1, 3

1 Neurochemistry Laboratory, 2 Alzheimer's Disease Research Laboratory, and 3 Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, 4 Experimental Neuropharmacology Laboratory, Department of Neurology, University of Tübingen, D-72076 Tübingen, Germany, and 5 Glaxo Institute for Molecular Biology S.A., CH-1228 Plan-les-Ouates, Geneva, Switzerland

The proto-oncogene Bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that Bcl-2 protects against free radicals and that it increases mitochondrial calcium-buffering capacity. The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride (MPTP) is thought to involve both mitochondrial dysfunction and free radical generation. We therefore investigated MPTP neurotoxicity in both Bcl-2 overexpressing mice and littermate controls. MPTP-induced depletion of dopamine and loss of [3H]mazindol binding were significantly attenuated in Bcl-2 overexpressing mice. Protection was more profound with an acute dosing regimen than with daily MPTP administration over 5 d. 1-Methyl-4-phenylpyridinium (MPP+) levels after MPTP administration were similar in Bcl-2 overexpressing mice and littermates. Bcl-2 blocked MPP+-induced activation of caspases. MPTP-induced increases in free 3-nitrotyrosine levels were blocked in Bcl-2 overexpressing mice. These results indicate that Bcl-2 overexpression protects against MPTP neurotoxicity by mechanisms that may involve both antioxidant activity and inhibition of apoptotic pathways.

Key words: MPTP; Parkinson's disease; apoptosis; free radicals; 3-nitrotyrosine; caspases; Bcl-2

Copyright © 1998 Society for Neuroscience  0270-6474/98/18208145-08$05.00/0


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