Endogenous melatonin protects L-DOPA from autoxidation in the striatal extracellular compartment of the freely moving rat: potential implication for long-term L-DOPA therapy in Parkinson's disease

Abstract:  We previously showed, using microdialysis, that autoxidation of exogenous L-dihydroxyphenylalanine (l-DOPA) occurs in vivo in the extracellular compartment of the freely moving rat, with a consequent formation of l-DOPA semiquinone (l-DOPA-SQ). In the present study, intrastriatal infusion of l-DOPA (1.0 μm for 200 min) increased dialysate l-DOPA concentrations (maximum increases up to 116-fold baseline values); moreover, l-DOPA-SQ was detected in dialysates. Individual dialysate concentrations of l-DOPA were negatively correlated with those of l-DOPA-SQ. Co-infusion of N-acetylcysteine (100 μm) or melatonin (50 μm) increased l-DOPA (up to 151- and 246-fold, respectively) and decreased l-DOPA-SQ (by about 53% and 87%, respectively) dialysate concentrations. Systemic l-DOPA [25 mg/kg intraperitoneally (i.p.) twice in a 12-h interval] significantly increased striatal baseline dialysate concentrations of l-DOPA and decreased dopamine (DA) and ascorbic acid (AsAc) concentrations, when compared with controls. Following systemic l-DOPA, l-DOPA-SQ was detected in dialysates. Endogenous melatonin was depleted in rats maintained on a 24-h light cycle for 1 wk. In melatonin-depleted rats, systemic l-DOPA induced a smaller increase in dialysate l-DOPA, a greater increase in l-DOPA-SQ formation, and a greater reduction in DA and AsAc dialysate concentrations. Co-administration of melatonin (5.0 mg/kg, i.p., twice in a 12-h interval) with l-DOPA, in control as well as in light-exposed rats, significantly increased dialysate l-DOPA concentrations, greatly inhibited l-DOPA-SQ formation, and restored up to the control values dialysate DA and AsAc concentrations. These findings demonstrate that endogenous melatonin protects exogenous l-DOPA from autoxidation in the extracellular compartment of the striatum of freely moving rats; moreover, systemic co-administration of melatonin with l-DOPA markedly increases striatal l-DOPA bioavailability in control as well as in melatonin-depleted rats. These results may be of relevance to the long-term l-DOPA therapy of Parkinson's disease.