The neurotoxicity of 1-methyl-4-phenylpyridinium in cultured cerebellar granule cells.
Cerebellar granule cells in enriched primary culture are susceptible to the neurotoxic effects of 1-methyl-4-phenylpyridinium (MPP+). Relatively high MPP+ concentrations are required to elicit neurotoxic effects at early culture times, but lower concentrations of MPP+ produce comparable neurotoxic effects at later culture times. Under identical culture conditions 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is not neurotoxic. Preincubation with the glutamate uptake blockers, DL-threo-3-hydroxyaspartic acid or dihydrokainate, or the dopaminergic uptake blocker mazindol, protects the granule cells from the cytotoxic effects of MPP+. Although MPTP is not neurotoxic in an enriched granule cell culture, in coculture with cerebellar astrocytes MPTP is toxic to granule cells, presumably because it is converted in astrocytes to MPP+. Cerebellar astrocytes remain confluent and viable. The addition of pargyline to the coculture abolishes the neurotoxicity consistent with a role of MAO B in bioactivation of MPTP. The concentration of MPP+ in the coculture medium (13 microM) was less than that required for the toxic effect in enriched neuronal cultures at earlier culture times, suggesting that an astroglial-neuronal interaction, perhaps by proximity, enhances the neurotoxicity of MPP+. These results might explain reported effects of MPTP on some cerebellar cells in mice.
Marini
A M
AM
Clinical Neurosciences Branch, National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland 20892.
Schwartz
J P
JP
Kopin
I J
IJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000506:poisoning*; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology / Q000031:analogs & derivatives; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D015198:Designer Drugs; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D006098:Granulocytes / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008995:Monoamine Oxidase / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D009994:Osmolar Concentration; D013997:Time Factors
D015198:Designer Drugs; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; C011274:3-hydroxyaspartic acid; D001224:Aspartic Acid; D018698:Glutamic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium