Neurotoxicity of a methylated analog of MPTP in mice

Conference · Sat Mar 01 04:00:00 EST 1986 · Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States)

OSTI ID:5430672

Heikkila, R E; Youngster, S K; Kindt, M V; Sonsalla, P K

Under conditions in which the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was relatively ineffective, (2 injections per day at 6-hr intervals on 2 successive days; total dose of 0.45 mmoles/kg) a methylated analog of MPTP, namely 2'CH/sub 3/-MPTP, produced a marked depletion in the neostriatal content of dopamine (DA) and its metabolites, a corresponding reduction of /sup 3/H-DA uptake into neostriatal synaptosomes, and an extensive loss of neurons in the pars compacta of the substantia nigra. 2'CH/sub 3/-MPTP is oxidized in vitro by monoamine oxidase-B in brain mitochondrial preparations, although at a much faster rate than is MPTP. And like the MPTP metabolite (MPP/sup +/), 1-methyl-4-(2'methylphenyl)pyridinium (2'CH/sub 3/-MPP/sup +/) is an excellent substrate for the DA transport system (as evidenced by its ability to release previously accumulated /sup 3/H-DA from synaptosomes, and the ability of the dopamine uptake inhibitor, mazindol, to prevent this release). In vivo, the pretreatment of mice with DA uptake inhibitors or monoamine oxidase-B inhibitors attenuated the above-mentioned biochemical changes induced by 2'CH/sub 3/-MPTP. It appears as if 2'CH/sub 3/-MPTP produces neurotoxicity in a manner similar to MPTP. That 2'CH/sub 3/-MPTP is oxidized at a faster rate than MPTP likely contributes to the fact that it is more potent than MPTP, although most certainly, other unknown considerations also are relevant.

• Research Organization: Rutgers Medical School, Piscataway, NJ
• OSTI ID: 5430672
• Report Number(s): CONF-8604222-
• Conference Information: Journal Name: Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States) Journal Volume: 45:3
• Country of Publication: United States
• Language: English

Related Subjects

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560305* -- Chemicals Metabolism & Toxicology-- Vertebrates-- (-1987)
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AMINES
ANIMAL CELLS
ANIMALS
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZINES
BODY
BRAIN
CARDIOTONICS
CARDIOVASCULAR AGENTS
CENTRAL NERVOUS SYSTEM
DOPAMINE
DRUGS
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
METABOLISM
METABOLITES
MICE
NERVE CELLS
NERVOUS SYSTEM
NEUROREGULATORS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
OXIDOREDUCTASES
PHENOLS
POLYPHENOLS
PYRIDINES
RODENTS
SOMATIC CELLS
SYMPATHOMIMETICS
TOXICITY
TRACER TECHNIQUES
TRITIUM COMPOUNDS
UPTAKE
VERTEBRATES