Correlation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood-brain barrier monoamine oxidase activity

Journal Article · Fri May 01 04:00:00 EDT 1987 · Proc. Natl. Acad. Sci. U.S.A.; (United States)

DOI:https://doi.org/10.1073/pnas.84.10.3521· OSTI ID:5595235

Kalaria, R N; Mitchell, M J; Harik, S I

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and subhuman primates, but not in rats and many other laboratory animals; mice are intermediate in their susceptibility. Since MPTP causes selective dopaminergic neurotoxicity when infused directly into rat substantia nigra, the authors hypothesized that systemic MPTP may be metabolized by monoamine oxidase and/or other enzymes in rat brain capillaries and possibly other peripheral organs and thus prevented from reaching its neuronal sites of toxicity. They tested this hypothesis by assessing monoamine oxidase in isolated cerebral microvessels of humans, rats, and mice by measuring the specific binding of (/sup 3/H)pargyline, an irreversible monoamine oxidase inhibitor, and by estimating the rates of MPTP and benzylamine oxidation. (/sup 3/H)Pargyline binding to rat cerebral microvessels was about 10-fold higher than to human or mouse microvessels. Also, MPTP oxidation by rat brain microvessels was about 30-fold greater than by human microvessels; mouse microvessels yielded intermediate values. These results may explain, at least in part, the marked species differences in susceptibility to systemic MPTP. They also suggest the potential importance of enzyme barriers at the blood-brain interface that can metabolize toxins not excluded by structural barriers, and may provide biological bases for developing therapeutic strategies for the prevention of MPTP-induced neurotoxicity and other neurotoxic conditions including, possibly, Parkinson's disease.

• Research Organization: Case Western Reserve Univ. School of Medicine, Cleveland, OH
• OSTI ID: 5595235
• Journal Information: Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 84:10; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

551001* -- Physiological Systems-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINO ACIDS
ANIMALS
AZINES
BLOOD VESSELS
BLOOD-BRAIN BARRIER
BODY
BRAIN
CARBOXYLIC ACIDS
CARDIOVASCULAR SYSTEM
CENTRAL NERVOUS SYSTEM
CEREBRUM
CHEMICAL REACTIONS
CONFIGURATION INTERACTION
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
GLYCINE
HETEROCYCLIC COMPOUNDS
LABELLED COMPOUNDS
MAMMALS
MAN
MICE
NERVOUS SYSTEM
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
OXIDATION
OXIDOREDUCTASES
OXYGENASES
PRIMATES
PYRIDINES
RATS
RODENTS
TOXICITY
TRITIUM COMPOUNDS
VERTEBRATES