Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease.
Dopamine (DA)- or L-dihydroxyphenylalanine-(L-DOPA-) induced neurotoxicity is thought to be involved not only in adverse reactions induced by long-term L-DOPA therapy but also in the pathogenesis of Parkinson's disease. Numerous in vitro and in vivo studies concerning DA- or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of DA induce neuronal damage and/or apoptotic or non-apoptotic cell death; the DA-induced damage is prevented by various intrinsic and extrinsic antioxidants. DA and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells mainly due to the generation of highly reactive DA and DOPA quinones which are dopaminergic neuron-specific cytotoxic molecules. DA and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. For example, the formation of DA quinone-alpha-synuclein consequently increases cytotoxic protofibrils and the covalent modification of tyrosine hydroxylase by DA quinones. The melanin-synthetic enzyme tyrosinase in the brain may rapidly oxidize excess amounts of cytosolic DA and L-DOPA, thereby preventing slowly progressive cell damage by auto-oxidation of DA, thus maintainng DA levels. Since tyrosinase also possesses catecholamine-synthesizing activity in the absence of tyrosine hydroxylase (TH), the double-edged synthesizing and oxidizing functions of tyrosinase in the dopaminergic system suggest its potential for application in the synthesis of DA, instead of TH in the degeneration of dopaminergic neurons, and in the normalization of abnormal DA turnover in the long-term L-DOPA-treated Parkinson's disease patients.
Asanuma
Masato
M
Department of Brain Science, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan. asachan@cc.okayama-u.ac.jp
Miyazaki
Ikuko
I
Ogawa
Norio
N
D000818:Animals; D004298:Dopamine / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000378:metabolism*; D015259:Dopamine Agents / Q000009:adverse effects*; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D010300:Parkinson Disease / Q000378:metabolism*
D015259:Dopamine Agents; D005609:Free Radicals; D007980:Levodopa; C104705:dopamine quinone; D014442:Monophenol Monooxygenase; D004298:Dopamine