The parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) mediates release of l-3,4-dihydroxyphenylalanine (l-DOPA) and inhibition of l-DOPA decarboxylase in the rat striatum: a microdialysis study.

Reactive oxygen species and reactive nitrogen species particularly peroxynitrite, have been implicated as key participants in the dopaminergic neurotoxicity of 1-methyl-4-phenylpyridinium (MPP(+)). However, on the basis of available information, it is not clear whether the MPP(+)-induced overproduction of and occurs in the intraneuronal and/or extracellular compartment. Early steps in the neurotoxic mechanism evoked by MPP(+) include a profound dopaminergic energy impairment, which mediates a massive release of dopamine (DA), glutathione (GSH), and cysteine (CySH). In the event that MPP(+) mediates extracellular generation of duanyu1670 (such as superoxide and/or hydroxyl radicals) and/or peroxynitrite, released DA, GSH, and CySH should be oxidized forming thioethers of DA and disulfides. Using microdialysis experiments in which MPP(+) was perfused into the striatum of awake rats, the present study was unable to detect the presence of such biomarkers of extracellular duanyu1670 and/or duanyu1668 generation. However, MPP(+) induced a transient, concentration-dependent rise of extracellular l-3,4-dihydroxyphenylalanine (l-DOPA), identified on the basis of dialysate analysis using several HPLC methods and its conversion to DA by purified l-DOPA decarboxylase (DDC). Methamphetamine (30 mg/kg, i.p.) similarly caused a significant but transient rise of l-DOPA in the rat striatum. Antioxidants such as salicylate and mannitol had no effect on the MPP(+)-mediated elevation of extracellular l-DOPA, suggesting that it is not formed by nonenzymatic hydroxylation of l-tyrosine by duanyu1670 or Rather, in vivo, but not in vitro, MPP(+) caused rapid inhibition of DDC, which appears to result in intraneuronal accumulation and subsequent release of l-DOPA. Because l-DOPA can mediate l-glutamate release, as well as be an excitotoxin, the possibility is raised that l-DOPA may play a role in the dopaminergic neurotoxicity of MPP(+).

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