Mptp, Mitochondria and Aging

Duvoisin, Roger C.

Abstract

The long-term goal of this project is to understand some of the basic mechanisms underlying the cellular degeneration which is a major feature of several neurological disorders, including Parkinson's (PD) and related diseases. The dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces an animal model of PD. The actual toxic agent in producing a lesion in the substantia nigra is thought to be its metabolite, 1-methyl-4-phenylpyridinium (MPP+). In this proposal various aspects of the hypothesis that MPP+ acts to kill cells by inhibiting mitochondrial metabolism at Site 1 of the electron transport chain will be further examined. It has been suggested that PD and some other degenerative disorders involve an abiotrophic interaction of aging and environmental factors. Therefore, the effects of MPTP/MPP+ on preparations from aged mice will also be studied. Specifically, the uptake of 3H-MPP+ by mitochondria will be measured in the presence of various analogs of MPP+ as well as in the presence of other organic cations such as chloroquine. The effect of these substances on the MPP+- induced inhibition of Site 1 respiration will also be studied. Mitochondria from synaptic endings will be compared to """"""""bulk""""""""- isolated brain mitochondria as well as liver mitochondria. These experiments will furnish important information as to the nature of the membrane carrier system for MPP+ and similar cations. The inhibition of aerobic glycolysis by MPTP, MPP+ and their analogs will be studied in tissue slices and synaptosomes from striatum and other brain areas. MAO-A/B inhibitors and dopamine uptake blockers will be used with these analogs to determine which factors (metabolism, uptake or mitochondrial inhibitory potency) are the principal determinant of inhibition. Using fluorescence probes, the effects of MPTP/MPP+ on intracellular free calcium concentration and mitochondrial membrane potential will be correlated with actual cell toxicity. The studies on effects of MPTP/MPP+ on mitochondria, tissue slices and synaptosomes will be compared in preparations from mice of different ages, including aged mice.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Neurological Disorders and Stroke (NINDS)
• Type: Research Program Projects (P01)
• Project #: 5P01NS021469-08
• Application #: 3846786
• Support Year: 8
• Fiscal Year: 1992

Institution

• Name: University of Medicine & Dentistry of NJ
• DUNS #: 622146454
• City: Piscataway
• State: NJ
• Country: United States
• Zip Code: 08854

Publications

Basma, A N; Morris, E J; Nicklas, W J et al. (1995) L-dopa cytotoxicity to PC12 cells in culture is via its autoxidation. J Neurochem 64:825-32

Gluck, M R; Youngster, S K; Ramsay, R R et al. (1994) Studies on the characterization of the inhibitory mechanism of 4'-alkylated 1-methyl-4-phenylpyridinium and phenylpyridine analogues in mitochondria and electron transport particles. J Neurochem 63:655-61

Giovanni, A; Sieber, B A; Heikkila, R E et al. (1994) Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 1: Systemic administration. J Pharmacol Exp Ther 270:1000-7

Okoye, G S; Freed, W J; Geller, H M (1994) Short-term immunosuppression enhances the survival of intracerebral grafts of A7-immortalized glial cells. Exp Neurol 128:191-201

Gluck, M R; Krueger, M J; Ramsay, R R et al. (1994) Characterization of the inhibitory mechanism of 1-methyl-4-phenylpyridinium and 4-phenylpyridine analogs in inner membrane preparations. J Biol Chem 269:3167-74

Giovanni, A; Sonsalla, P K; Heikkila, R E (1994) Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 2: Central administration of 1-methyl-4-phenylpyridinium. J Pharmacol Exp Ther 270:1008-14

Basma, A N; Heikkila, R E; Saporito, M S et al. (1992) 1-Methyl-4-(2'-ethylphenyl)-1,2,3,6-tetrahydropyridine-induced toxicity in PC12 cells is enhanced by preventing glycolysis. J Neurochem 58:1052-9

Saporito, M S; Heikkila, R E; Youngster, S K et al. (1992) Dopaminergic neurotoxicity of 1-methyl-4-phenylpyridinium analogs in cultured neurons: relationship to the dopamine uptake system and inhibition of mitochondrial respiration. J Pharmacol Exp Ther 260:1400-9

Sonsalla, P K; Zeevalk, G D; Manzino, L et al. (1992) MK-801 fails to protect against the dopaminergic neuropathology produced by systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice or intranigral 1-methyl-4-phenylpyridinium in rats. J Neurochem 58:1979-982

Geller, H M; Quinones-Jenab, V; Poltorak, M et al. (1991) Applications of immortalized cells in basic and clinical neurology. J Cell Biochem 45:279-83