Protective Effects of Nicotine Against Aminochrome-Induced Toxicity in Substantia Nigra Derived Cells: Implications for Parkinson’s Disease

Abstract

Parkinson’s disease is a debilitating progressive neurodegenerative disorder that results from the loss of or damage to dopaminergic cells containing neuromelanin in the substantia nigra (SN). The underlying neurodegenerative mechanism(s), however, remain elusive. Aminochrome, the precursor of neuromelanin is an endogenous substance capable of inducing selective neurotoxicity to dopaminergic neurons in SN. Nicotine, on the other hand, may offer protective effects against dopaminergic cell damage induced by various neurotoxins including MPTP and salsolinol. In this study, we sought to determine whether nicotine may also protect against aminochrome-induced toxicity in SN derived RCSN-3 cells. Exposure of RCSN-3 cells to a combination of aminochrome (50 μM) and dicoumarol (50 μM) for 48 h induced approximately 70 % cell death. Pretreatment with nicotine, dose-dependently blocked this toxicity. The effects of nicotine in turn were dose-dependently blocked by mecamylamine, a non-selective nicotinic receptor antagonist. These results suggest involvement of nicotinic receptors in protective effects of nicotine against aminochrome-induced toxicity and provide further evidence for possible therapeutic effects of nicotine or nicotinic agonists in Parkinson’s disease.

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).…”

Molecular and Neurochemical Mechanisms Dopamine Oxidation To O-Quinones in Parkinson’s Disease Pathogenesis

“…Enzymatic GSH conjugation of dopamine o-quinone to 5-S-glutathionyl dopamine was catalyzed by GSTM2, although a non-enzymatic reaction has also been reported [43,55]. In contrast, other studies have involved aminochrome formation prior to the experiment [56] or the use of purified aminochrome [57][58][59][60][61][62]; thus, it is possible that 5,6-indolequinone had been formed in these experiments. However, the aminochrome conjugation with glutathione catalyzed by glutathione S-transferase M2 (GSTM2) generated only 4-S-glutathionyl-5,6-dihydroxyindoline and not 4-S-glutathionyl-5,6-dihydroxyindole, which should be the product of 5,6-indolequinone glutathione conjugation [63].…”

“…The depletion of NADPH results in a decrease in reduced glutathione because NADPH is required for the enzymatic reduction of glutathione. Several reports demonstrate that the one-electron reduction of aminochrome is a neurotoxic reaction both in cell cultures and in vivo [27,28,32,33,54,[56][57][58][59][60][61][62][81][82][83][84][85][86].…”

Duality of Antidepressants and Neuroprotectants

“…Moreover, in vitro and in vivo studies have shown that nicotine may protect against nigrostriatal damage induced by various compounds. Thus, 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; Ramlochansingh et al 2011; Munoz et al 2012). Similarly in animal studies, including non-human primates, it has been shown that nicotine delays Parkinson’s disease-like symptoms induced by MPTP (Quik et al 2006, 2009, 2014).…”