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.
References
Aguirre P, Urrutia P, Tapia V, Villa M, Paris I, Segura-Aguilar J, Núñez MT (2012) The dopamine metabolite aminochrome inhibits mitochondrial complex I and modifies the expression of iron transporters DMT1 and FPN1. Biometals (Epub ahead of print)
Arriagada C, Paris I, Sanchez de las Matas MJ, Martinez-Alvarado P, Cardenas S, Castañeda P, Graumann R, Perez-Pastene C, Olea-Azar C, Couve E, Herrero MT, Caviedes P, Segura-Aguilar J (2004) On the neurotoxicity mechanism of leukoaminochrome o-semiquinone radical derived from dopamine oxidation: mitochondria damage, necrosis, and hydroxyl radical formation. Neurobiol Dis 16:468–477
Copeland RL Jr, Leggett YA, Kanaan YM, Taylor RE, Tizabi Y (2005) Neuroprotective effects of nicotine against salsolinol-induced cytotoxicity: implications for Parkinson’s disease. Neurotox Res 8:289–293
Copeland RL Jr, Das JR, Kanaan YM, Taylor RE, Tizabi Y (2007) Antiapoptotic effects of nicotine in its protection against salsolinol-induced cytotoxicity. Neurotox Res 12:61–69
Das JR, Tizabi Y (2009) Additive protective effects of donepezil and nicotine against salsolinol-induced cytotoxicity in SH-SY5Y cells. Neurotox Res 16:194–204
Dehay B, Bezard E (2011) New animal models of Parkinson’s disease. Mov Disord 26:1198–1205
LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11:1159–1161
Muñoz P, Paris I, Sanders LH, Greenamyre JT, Segura-Aguilar J (2012) Over expression of VMAT-2 and DT-diaphorase protect susbtantia nigra-derived cells against aminochrome neurotoxicity. Biochim Biophys Acta (Epub ahead of print)
Norris EH, Giasson BI, Hodara R, Xu S, Trojanowski JQ, Ischiropoulos H, Lee VM (2005) Reversible inhibition of alpha-synuclein fibrillization by dopaminochrome-mediated conformational alterations. J Biol Chem 280:21212–21219
Paris I, Cardenas S, Lozano J, Perez-Pastene C, Graumann R, Riveros A, Caviedes P, Segura-Aguilar J (2007) Aminochrome as a preclinical experimental model to study degeneration of dopaminergic neurons in Parkinson’s disease. Neurotox Res 12:125–134
Paris I, Lozano J, Cardenas S, Perez-Pastene C, Saud K, Fuentes P, Caviedes P, Dagnino-Subiabre A, Raisman-Vozari R, Shimahara T, Kostrzewa JP, Chi D, Kostrzewa RM, Caviedes R, Segura-Aguilar J (2008) The catecholaminergic RCSN-3 cell line: a model to study dopamine metabolism. Neurotox Res 13:221–230
Paris I, Perez-Pastene C, Cardenas S, Iturriaga-Vasquez P, Muñoz P, Couve E, Caviedes P, Segura-Aguilar J (2010) Aminochrome induces disruption of actin, alpha-, and beta-tubulin cytoskeleton networks in substantia-nigra-derived cell line. Neurotox Res 18:82–92
Paris I, Muñoz P, Huenchuguala S, Couve E, Sanders LH, Greenamyre JT, Caviedes P, Segura-Aguilar J (2011) Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line. Toxicol Sci 121:376–388
Quik M, O’Leary K, Tanner CM (2008) Nicotine and Parkinson’s disease: implications for therapy. Mov Disord 23:1641–1652
Ramlochansingh C, Taylor RE, Tizabi Y (2011) Toxic effects of low alcohol and nicotine combinations in SH-SY5Y cells are apoptotically mediated. Neurotox Res 20:263–269
Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26:1049–1055
Segura-Aguilar J, Metodiewa D, Welch C (1998) Metabolic activation of dopamine o-quinones to o-semiquinones by NADPH cytochrome P450 reductase may play an important role in oxidative stress and apoptotic effects. Biochim Biophys Acta 1381:1–6
Van Laar VS, Mishizen AJ, Cascio M, Hastings TG (2009) Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. Neurobiol Dis 34:487–500
Zafar KS, Siegel D, Ross D (2006) A potential role for cyclized quinones derived from dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid in proteasomal inhibition. Mol Pharmacol 70:1079–1086
Acknowledgments
This study was supported by FONDECYT #1100165 (JSA), NIH/NIGMS (2SO6 GM08016-39 (YT), and NIH-RCMI 2 G12 RR003048 (YT).
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Muñoz, P., Huenchuguala, S., Paris, I. et al. Protective Effects of Nicotine Against Aminochrome-Induced Toxicity in Substantia Nigra Derived Cells: Implications for Parkinson’s Disease. Neurotox Res 22, 177–180 (2012). https://doi.org/10.1007/s12640-012-9326-7
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DOI: https://doi.org/10.1007/s12640-012-9326-7