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Astrocytes as a primary locus for the conversion MPTP into MPP+
W J Brooks1, M F Jarvis, G C Wagner
1Department of Psychology, Rutgers, State University, New Brunswick, New Jersey.
Abstract:
The enzymatic conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion by monoamine oxidase-B is an essential step mediating the dopaminergic neurotoxicity. Since monoamine oxidase-B is located primarily in serotonergic neurons and astrocytes, the production of 1-methyl-4-phenylpyridinium ion is thought to be extra-dopaminergic. This study provides evidence in support of this conclusion. Pretreating mice with fluoxetine (a serotonergic uptake inhibitor) before the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine attenuated the dopaminergic neurotoxicity. This was not the result of a nonspecific inhibition of dopaminergic uptake, as fluoxetine pretreatment did not attenuate the dopaminergic neurotoxicity resulting from the intrastriatal administration of the 1-methyl-4-phenylpyridinium ion. Further localization of the primary site of 1-methyl-4-phenylpyridinium ion production as being astrocytes was provided by the failure of 5,7-dihydroxytryptamine-induced serotonergic lesions to attenuate the neurotoxicity produced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, whereas, fluoxetine pretreatment in similarly lesioned subjects, continued to attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. These results are consistent with the hypothesis that astrocytes are a principle site of 1-methyl-4-phenylpyridinium ion production.
Insights
Monoamine oxidase-B converts MPTP to MPP+, causing neurotoxicity. This study shows astrocytes, not dopamine neurons, are the primary site of this conversion, evidenced by fluoxetine
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Monoamine oxidase-B (MAO-B) mediates dopaminergic neurotoxicity via MPTP conversion.
- MAO-B's presence in serotonergic neurons and astrocytes suggests extra-dopaminergic MPP+ production.
Purpose of the Study:
- To investigate the primary site of MPP+ production and its role in neurotoxicity.
- To determine if astrocytes are the main site for MPP+ synthesis.
Main Methods:
- Mice were pretreated with fluoxetine (serotonin uptake inhibitor) before MPTP administration.
- Neurotoxicity was assessed after intrastriatal MPP+ administration.
- Serotonergic neurons were lesioned using 5,7-dihydroxytryptamine.
Main Results:
- Fluoxetine pretreatment attenuated MPTP-induced neurotoxicity.
- Fluoxetine did not affect neurotoxicity from direct MPP+ administration.
- Serotonergic lesions did not prevent MPTP neurotoxicity, but fluoxetine still provided protection.
Conclusions:
- Astrocytes are a principal site for MPP+ production.
- MPP+ neurotoxicity is primarily mediated by extra-dopaminergic pathways involving astrocytes.