The Parkinsonian Neurotoxin 1-Methyl-4-Phenylpyridinium (MPP⁺) Mediates Release ofl-3,4-Dihydroxyphenylalanine (l-DOPA) and Inhibition ofl-DOPA Decarboxylase in the Rat Striatum:  A Microdialysis Study

Abstract

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(+).

Induction of Phenotypes Resembling CuZn-Superoxide Dismutase Deletion in Wild-Type Yeast Cells: An in Vivo Assay for the Role of Superoxide in the Toxicity of Redox-Cycling Compounds

“…We believe that the methionine auxotrophy must result from something other than excess superoxide. For example, MPP + is thought to deplete GSH in some systems (39,53,54), and methionine is a good source of reduced sulfur, so it is possible that in the absence of methionine growth is slowed because the cells must devote significantly more energy to processing sulfur for GSH synthesis. Alternatively, MPP + may specifically inhibit some step in methionine synthesis or deplete NADPH in another way.…”

“…It is the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes symptoms resembling Parkinson's disease in humans and other mammals (). There has been some controversy over its mode(s) of toxicity; in vitro data have argued against redox cycling ( , ) while in vivo data suggest that MPP + treatment may result in superoxide stress either directly or by inhibition of complex I ( − ). Other studies implicate MPP + as causing mitochondrial dysfunction through a change in membrane potential, redox status, or energy metabolism ( − ).…”

Increased extracellular glutamate evoked by 1-Methyl-4-phenylpyridinium (MPP+) in the rat striatum is not essential for dopaminergic neurotoxicity and is not derived from released glutathione

“…Furthermore, the large dose-dependent increase of extracellular Glu levels evoked by perfusions of ≥ 2.5 mM MPP + is not the result of the γ-GT-mediated hydrolysis of released GSH. In our earlier report (Foster et al, 2003) it was shown that 30 min perfusions of ≥ 1.3 mM MPP + into the striatum of awake rats evoked not only damage to dopaminergic terminals but also to serotonergic fibers. The present study provides evidence that MPP + may also be toxic to astrocytes and, at high concentrations, is an indiscriminate cellular toxin.…”

“…2B). In an earlier report (Foster et al, 2003) we have shown that perfusion of MPP + into the rat striatum mediates a dosedependent, slightly delayed, transient but significant rise of microdialysate levels of L-3,4-dihydroxyphenylalanine (L-DOPA), a rapid decrease of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and an initial brief elevation of 3-methyoxytyramine (3-MT) followed by its subsequent decline. Acivicin (1 mM) had no significant effects on these neurochemical changes evoked by MPP + (data not shown).…”

Green and efficient determination of ʟ-dopa in complex polypill formulations using a magnetic microplate

“…This compound is the most efficacious and best-tolerated treatment for Parkinson's disease, which is caused by a significant depletion of dopamine resulting from the death of dopamine-producing neurons in the brain. However, as dopamine cannot penetrate the brain-blood barrier, ʟ-dopa therapy is employed to treat this disease (1). More specifically, ʟ-dopa is rapidly converted into dopamine in peripheral tissue through the action of dopamine decarboxylase enzymes.…”