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 (ROS) and reactive nitrogen species (RNS), 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 ROS and RNS 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 ROS (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 ROS and/or RNS 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 ROS or RNS. 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(+).
Foster
Steven B
SB
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019-0370, USA.
Wrona
Monika Z
MZ
Han
Jilin
J
Dryhurst
Glenn
G
D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001831:Body Temperature; D002851:Chromatography, High Pressure Liquid; D004296:Dopa Decarboxylase / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000139:chemically induced*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D012459:Salicylates; D012701:Serotonin; D008353:Mannitol; D007980:Levodopa; D006897:Hydroxyindoleacetic Acid; D004296:Dopa Decarboxylase; D015655:1-Methyl-4-phenylpyridinium