Intervention of mitochondrial dysfunction-oxidative stress-dependent apoptosis as a possible neuroprotective mechanism of alpha-lipoic acid against rotenone-induced parkinsonism and L-dopa toxicity
Amany Abd El-Rahim Abdin
Department of Pharmacology
Faculty of Medicine, Tanta University, Egypt
Abstract:
The current study evidenced the hypothesis that mitochondrial dysfunction-oxidative stress-dependent apoptotic pathways play a critical role in degeneration of dopaminergic neurons in parkinson''s disease (PD). Model of rotenone-induced parkinsonism in rats given i.p. in a dose of 2.5 mg/kg once daily for 60 days produced significant decrease in striatal complex I activity and levels of reduced glutathione (GSH) with significant increase in striatal nitrites concentration as well as caspase-3 activity. This was confirmed by the significant negative correlation of catalepsy score after 60 days (either grid test or bar test; respectively) with complex I activity and GSH levels, while it showed significant positive correlation with the striatal nitrites concentration and caspase-3 activity. Moreover, the electron microscopic examination of striatal neurons displayed wide range of affection was seen as multiple neurons with hyperchromatic nuclei and electron dense or disrupted mitochodria. L-Dopa is still viewed as a gold standard replacement therapy that provids symptomatic relieve, but it is proved to accelerate the underlying neuronal degeneration by way of oxidative metabolism. Its administration in a dose of 10 mg/kg/day by oral gavage, started 20 days after induction of parkinsonism and continued till 60 days; although caused marked symptomatic improvement in catalepsy score, but there is further worsening in the measured neurochemical parameters. Therefore, efforts are made not only to improve the effect of L-Dopa treatment for PD, but also to introduce new drugs with both antiparkinsonian and neuroprotective effects. When alpha-lipoic acid (LA) was investigated in this study; it exhibited noticeable neuroprotective effects when administered by oral gavage in a dose of 100 mg/kg/day 1 hour before rotenone. The mechanism of this neuroprotection was proved to be via intervention of the mitochondrial dysfunction-oxidative stress-dependent apoptotic pathways; where it caused significant increase in striatal complex I activity and levels of GSH with significant decrease in striatal nitrites concentration as well as caspase-3 activity and the electron microscopic examination revealed many normal looking neurons with few affected ones. The improvement in catalepsy score by alpha-lipoic acid -although still worse than normal- pointing to its disease-modifying effects. Combination of alpha-lipoic acid with L-Dopa revealed normalization of catalepsy score in addition to amelioration of the measured neurochemical parameters indicating the benefit of a full symptomatic and neuroprotective therapy. In conclusion, alpha-lipoic acid could be recommended as a promising disease-modifying therapy with L-dopa when given early in the course of parkinson''s disease.
