Differences in the disposition and toxicity of 1-methyl-4-phenylpyridinium in cultured rat and mouse astrocytes

Species difference in the susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was investigated in cultured rat and mouse astrocytes, where 1-methyl-4-phenylpyridinium (MPP⁺), the toxic mediator of MPTP, is formed. Type A monoamine oxidase (MAO) predominated in both rat and mouse astrocytes, while its activity was slightly higher in mouse cells compared to rat cells; MAO-B activity, on the other hand, was significantly lower in mouse astrocytes than in rat astrocytes. Because both types of MAO have been reported to make similar contributions to MPP⁺ production in astrocytes, their total activity was examined and results indicated that there was no significant difference between these two species. In additon, MPP^± caused a dose dependent loss of cell viability as judged by the amount of lactate dehydrogenase released into the incubation medium. The toxicity of MPP^± on astrocytes started to be seen after a 2 day incubation period. Mouse astrocytes were more vulnerable to MPP^± than rat astrocytes. The threshhold values for MPP^± toxicity in mouse and rat cultures were 10 ±M and 70 ±M, respectively. After addition of [³H] MPP^± to the medium, intracellular [³H] MPP^± was found to increase in both cultures. Mouse astrocytes accumulated more MPP^± than rat astrocytes (150 pmol/mg protein vs. 65 pmol/mg protein). When astrocytes were allowed to accumulate [³H] MPP^± and then incubated in fresh medium medium not containing [³H] MPP^±, intracellular levels of [³H] MPP^± in both cells rapidly declined (110 pmol/protein in mouse vs. 40 pmol/mg protein in rat of MPP^± been released). These results indicated that (1) MPP^± could cross the plasma membrane of astrocytes despite of its charged chemical structure, (2) mouse astrocytes had a higher capacity for MPP^± accumulation (approximately 2-fold), as well as release (approximately 2.7-fold), than rat astrocytes, and (3) mouse astrocytes were more vulnerable to MPP^± than rat astrocytes.