Additive Protective Effects of Donepezil and Nicotine Against Salsolinol-Induced Cytotoxicity in SH-SY5Y Cells

Abstract

Although the etiology of Parkinson's disease (PD) remains elusive, a number of toxins including elevated salsolinol, an endogenous metabolite of dopamine may contribute to its pathology. It was reported recently that nicotine may have protective effects against salsolinol-induced toxicity in human neuroblastoma derived SH-SY5Y cells and that these effects of nicotine are mediated by nicotinic receptors. Donepezil (Aricept) is a reversible non-competitive acetylcholinesterase inhibitor that is approved for use in mild to moderate Alzheimer's disease. The increase in acetylcholine concentrations is believed to be the major contributory factor in donepezil's therapeutic efficacy. However, cholinesterase inhibitors may also directly interact with nicotinic receptors and possess neuroprotective properties. In this study, we sought to determine whether donepezil may have protective effects against salsolinol-induced toxicity in SH-SY5Y cells and whether the combination of donepezil and nicotine may result in additive protection. Moreover, it was of interest to elucidate the role of nicotinic receptors as well as cell cycle and apoptosis in mechanism of action of these compounds. SH-SY5Y cells were exposed to 0.6 mM salsolinol with and without various drug pretreatments for 48 h. Nicotine (50 muM) resulted in approximately 54% protection and donepezil (5 muM) resulted in approximately 40% protection, and the combination of the two resulted in an additive (approximately 93%) protection against salsolinol-induced toxicity. Salsolinol caused an arrest of the cells in G(1)-phase of cell cycle and an increase in apoptotic indices that were blocked by the combination of donepezil and nicotine. Mecamylamine, a non-selective nicotinic receptor antagonist completely blocked the effects of nicotine and partially attenuated the effects of donepezil. A combination of atropine, a muscarinic receptor antagonist and mecamylamine completely blocked the effects of donepezil, indicating involvement of both nicotinic and muscarinic receptors in donepezil's actions. The findings suggest a therapeutic potential for the combination of donepezil and nicotine in PD.

Neuroprotective effect of carnosine against salsolinol-induced Parkinson's disease

“…The results of the current study indicated that salsolinol may induce neurotoxicity in the male albino rat brain and rat brain endothelial cells (34,35). Treatment with carnosine exhibited a significant improvement in neurotoxicity.…”

Neuroinflammation, Neurodegeneration, and Depression

“…In-vivo and in-vitro studies have shown that nicotine protects against nigrostriatal damage induced by various compounds. For example, in Parkinson's disease cell models nicotine protects against endogenous substances such as salsolinol and aminochrome that selectively damage dopaminergic cells (Copeland et al 2005, 2007; Das and Tizabi 2009; Muñoz et al 2012; Ramlochansingh et al 2011), and delays Parkinson's disease-like symptoms induced by MPTP in non-human primates (Quik et al 2006). Recently it has been suggested that nicotine protection against MPTP in a mouse model of Parkinson's disease is via inhibition of astrocyte activation (Liu et al 2012).…”

Protective Effects of Curcumin Against Rotenone and Salsolinol-Induced Toxicity: Implications for Parkinson’s Disease

“…These cells, derived from human neuroblastoma cells, are commonly used as an in-vitro model of the nigral dopaminergic cells (Copeland et al, 2007, Das and Tizabi, 2009, Xie et al, 2010, Ramlochansingh et al, 2011, Brown et al, 2013). Moreover, we evaluated possible contribution of apoptotic and/or necrotic mechanisms to the toxicity of these compounds and the protective effects of curcumin.…”