Potential Roles of Accelerated Dopamine Oxidation, Altered Glutathione Metabolism, 5-S-Cysteinyl-Dopamine and its Oxidative Metabolites in the Pathogenesis of Parkinson’s Disease

摘要: Many factors appear to be involved in the neurotoxic mechanism that underlies degeneration of neuromelanin-pigmented dopaminergic neurons substantia nigra pars compacta (SNpc) Parkinson’s disease (PD). These include: (1) a massive loss glutathione (GSH) without corresponding increases disulfide, very early change parkinsonian SNpc; (2) increased intraneuronal superoxide (O 2 -· ) generation; (3) mobilization low molecular weight iron from storage proteins, part which is scavenged by neuromelanin; (4) activity γ-glutamyl transpeptidase; (5) an accelerated rate dopamine (DA) oxidation does not lead neuromelanin deposition but rather formation 5-S-cysteinyldopamine (5-S-CyS-DA); and (6) decreased activities mitochondrial complex I α-ketoglutarate dehydrogenase (α-KGDH). Based on these changes information derived studies neurotoxicity 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine methamphetamine, new pathological proposed might contribute understanding SNpc cell death PD. This suggested initiated transient neuron energy impairment triggers cascade processes ultimately result DA O presence cysteine form 5-S-CyS-DA. Further mediated 5-S-CyS-DA aberrant dihydrobenzothiazine benzothiazine metabolites responsible for α-KGDH inhibition.