Lipoic acid alleviates L­DOPA­induced dyskinesia in 6­OHDA parkinsonian rats via anti­oxidative stress.

ABSTRACT

Levodopa (L­DOPA) is the gold standard for symptomatic treatment of Parkinson's disease (PD); however, long­term therapy is associated with the emergence of L­DOPA­induced dyskinesia (LID). Nigral dopaminergic cell loss determines the degree of drug exposure and time required for the initial onset of LID. Accumulating evidence indicates that α­lipoic acid (ALA) decreases this nigral dopaminergic cell loss. However, until now, the precise mechanisms of ALA have only been partially understood in LID. Chronic L­DOPA treatment was demonstrated to develop intense AIM scores to assess dyskinetic symptoms. Rats in the LID group were administrated twice daily with L­DOPA + benserazide for 3 weeks to induce a rat model of dyskinesia. Moreover, other 6­OHDA­lesioned rats were treatment with ALA (31.5 mg/kg or 63 mg/kg) in combination with L­DOPA treatment. Furthermore, the authors investigated the level of malondialdehyde (MDA) and glutathione (GSH) activity, as well as IBa­1, caspase­3 and poly (ADP-ribose) polymerase (PARP) in substantia nigra by the way of western blotting and immunofluorescence. ALA reduced LID in a dose­dependent manner without compromising the anti­PD effect of L­DOPA. Moreover, ALA reduced the level of MDA and upregulated the GSH activity, as well as ameliorated IBa­1 positive neurons in the substantia nigra. Finally, it was identified that ALA could reduce L­DOPA­induced cleaved­caspase­3 and PARP overexpression in the substantia nigra. Based on the present findings, ALA could be recommended as a promising disease­modifying therapy when administered with L­DOPA early in the course of PD. The exact mechanism for this action, although incompletely understood, appears to relate to anti­oxidative stress and anti­apoptosis.