Neuroscience Research 71 (2011) 387–395 Contents lists available at SciVerse ScienceDirect Neuroscience Research jo u r n al hom ep age: www.elsevier.com/locate/neures Intervention of mitochondrial dysfunction-oxidative stress-dependent apoptosis as a possible neuroprotective mechanism of -lipoic acid against rotenone-induced parkinsonism and l-dopa toxicity Amany A. Abdin a,∗ , Naglaa I. Sarhan b a Department of Pharmacology, Faculty of Medicine, Tanta University, Egypt b Department of Histology, Faculty of Medicine, Tanta University, Egypt a r t i c l e i n f o Article history: Received 30 June 2011 Received in revised form 18 August 2011 Accepted 18 August 2011 Available online 26 August 2011 Keywords: Parkinson’s disease -Lipoic acid l-Dopa Mitochondrial dysfunction Oxidative stress Apoptosis a b s t r a c t The current study evidenced hypothesis that mitochondrial dysfunction-oxidative stress-dependent apoptotic pathways play a critical role in degeneration of dopaminergic neurons in Parkinson’s disease. Model of rotenone-induced parkinsonism in rats produced decrease in striatal complex I activity and reduced glutathione with increase in nitrites concentration and caspase-3 activity. This was confirmed by significant correlation of catalepsy score with neurochemical parameters. Moreover, electron microscopic examination of striatal neurons displayed ultrastructure affection as hyperchromatic nuclei and disrupted mitochondria that are typical features of undergoing apoptosis. Administration of l-dopa as replacement therapy, although caused symptomatic improvement in catalepsy score, but further worsening in neu- rochemical parameters. Therefore, efforts are not only to improve effect of l-dopa, but also to introduce drugs provide antiparkinsonian and neuroprotective effects. In this study, -lipoic acid exhibited notice- able neuroprotective effects by a mechanism via intervention of mitochondrial dysfunction-oxidative stress-dependent apoptotic pathways. Combination of -lipoic acid efficiently halting deleterious toxic effects of l-dopa, revealed normalization of catalepsy score in addition to amelioration of neurochemi- cal parameters and apparent preservation of striatal ultrastructure integrity, indicating benefit of both symptomatic and neuroprotective therapy. In conclusion, -lipoic acid could be recommended as a disease-modifying therapy when given with l-dopa early in course of Parkinson’s disease. © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. 1. Introduction As one of neurodegenerative disorders, Parkinson’s disease (PD) afflicting approximately 6 million people worldwide and its inci- dence will rise considerably in the next future with increasing average life expectancy (Levy et al., 2009; Winklhofer and Haass, 2010). It is caused by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in deficiency of dopamine (DA) in the striatum and development of its characteristic motor symptoms as bradykinesia, rigidity and tremors. The etiology of neuronal death in PD still remains elu- sive. Various mechanisms of neuronal degeneration in PD have been proposed, including formation of free radicals, oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental ∗ Corresponding author at: Department of Pharmacology, Faculty of Medicine, Tanta University, Al-Geish Street, Postal No.: 31527, Egypt. Tel.: +20 123700963. E-mail addresses: amanyabdin@med.tanta.edu.eg, amanynhr@hotmail.com (A.A. Abdin). factors, toxic action of nitric oxide, and apoptosis. All these fac- tors interact with each other, inducing a vicious cycle of toxicity causing neuronal dysfunction, atrophy and finally cell death (Yuan et al., 2010). In this scenario, dysfunction of mitochondrial complex I leads to degeneration of dopaminergic neurons through activation of mitochondria-dependent apoptosis (programmed cell death) pathways (Vila and Perier, 2008). Although the brain is only 2–3% of the total body mass, but it consumes 20% of body oxygen. Cells in the brain are particularly susceptible to oxidative damage due to high levels of polyunsaturated fatty acids in their membranes and relatively low activity of endogenous antioxidant enzymes (Miller et al., 2009). The limited glycolytic capacity of neurons makes them highly dependent on aerobic oxidative phosphoryla- tion by mitochondria for their energetic needs (Moreira et al., 2010). The mitochondrial electron transport chain is a major site of reac- tive oxygen species (ROS) production in cells. Leakage of electrons directly to molecular oxygen results in generation of superoxide (O 2 •- ), and it is estimated that even under normal circumstances approximately 2–5% of oxygen consumed by mitochondria is con- verted to O 2 •- in these organelles. The observations suggest that when complex I deficiency persists in neurons over an extended 0168-0102/$ – see front matter © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. doi:10.1016/j.neures.2011.08.008