Antiapoptotic effects of nicotine in its protection against salsolinol-induced cytotoxicity.
ABSTRACT Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a metabolite of dopamine, may act as an endogenous neurotoxin and contribute to the etiology of Parkinson's disease (PD). The inverse relationship between smoking and PD prompted our previous investigation and the report of protective effects of nicotine against salsolinol-induced toxicity in cultured SH-SY5Y cells (Copeland et al., Neurotox. Res. 8:289, 2005). These cells, derived from human neuroblastoma cells, express dopaminergic activity and are used as a model of nigral dopaminergic cells, the major site of pathology in PD. The purpose of the current study was to investigate whether apoptotic or antiapoptotic mechanisms were responsible for the observed effects of salsolinol and nicotine, respectively. Moreover, it was of interest to determine whether the actions of nicotine are mediated through nicotinic receptors. SH-SY5Y cells were exposed to 0.4 or 0.7 mM salsolinol with and without pretreatment in combination of 0.1 mM nicotine and 0.1 mM mecamylamine and were exposed for 24 and 48 h. Various parameters including cell cycle perturbations (reflected in propidium iodide DNA staining); cell cycle regulator retinoblastoma protein (reflected in the Western blot), apoptosis (reflected in annexin V/propidium iodide staining followed by flow cytometry) were analyzed. Salsolinol caused an arrest of the cells in G1-phase of cell cycle and an increase in apoptotic indices, whereas pretreatment with nicotine attenuated or completely blocked the effects of salsolinol. Nicotine effects in turn, were totally blocked by mecamylamine (0.1 mM). The results suggest that apoptosis is a major mechanism for salsolinol-induced toxicity and that antiapoptotic effects of nicotine, mediated by nicotinic receptors, may play a primary role in its neuroprotective effects. Hence, nicotinic agonists in combination with other antiapoptotic agents may be of substantial benefit in at least a subpopulation of Parkinson patients.
- SourceAvailable from: Juan Segura-Aguilar[Show abstract] [Hide abstract]
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.Neurotoxicity Research 04/2012; 22(2):177-80. DOI:10.1007/s12640-012-9326-7 · 3.15 Impact Factor
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ABSTRACT: It is well established that combination of heavy drinking and smoking has severe health consequences. However, at relatively low concentrations, both alcohol and nicotine may have beneficial effects including neuroprotection. Thus, protective effects of low alcohol concentration against beta-amyloid-induced toxicity in organotypic hippocampal slices and protective effects of nicotine against salsolinol-induced toxicity in human-derived neuroblastoma cells (SH-SY5Y) have been reported. In this study, we sought to determine whether alcohol might also be protective against salsolinol-induced toxicity in SH-SY5Y cells and whether the combination of low doses of alcohol and nicotine might have an additive or synergistic effect. Pre-exposure of SH-SY5Y cells to either ethanol (1 or 10 mM) or nicotine (20 or 50 μM) significantly attenuated salsolinol-induced toxicity. However, contrary to the expectation the combination of low doses of alcohol and nicotine not only did not provide any synergistic or additive protective effect, but exacerbated salsolinol-induced toxicity. Indeed, simple combination of low alcohol and nicotine resulted in significant toxicity in SH-SY5Y cells. This toxicity, reflected in a reduction in cell viability was associated with an increase in apoptosis as determined by caspase-3 measurement. These in vitro results suggest that combination of even low concentrations of alcohol and nicotine may activate apoptotic mechanisms that can lead to cell toxicity and detrimental consequences.Neurotoxicity Research 10/2011; 20(3):263-9. DOI:10.1007/s12640-011-9239-x · 3.15 Impact Factor
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ABSTRACT: The observed high incidence of smoking amongst depressed individuals has led to the hypothesis of 'self medication" with nicotine in some of these patients. The inbred Wistar-Kyoto (WKY) rats exhibit depressive-like characteristics as evidenced by exaggerated immobility in the forced swim test (FST). One aim of this study was to investigate whether nicotine may have an antidepressant-like effect in these animals. Moreover, because of human postmortem studies indicating a reduction of the hippocampus volume in depressed patients, it was of interest to determine whether such an anatomical anomaly may also be manifested in WKY rats and whether it would be affected by chronic nicotine treatment. Adult female WKY and their control Wistar rats were administered nicotine consecutively (0.2 mg/kg, i.p., once or twice daily for 14 days) and their activity in an open field, as well as their immobility in FST were assessed either 15 min or 18 h after the last injection. Another set of animals was treated twice daily with 0.2 mg/kg nicotine for 14 days and sacrificed on day 15 for stereological evaluation of the hippocampal volume. When tested 15 min after the last injection, once or twice daily nicotine exacerbated the immobility in the FST in WKY rats only. When tested 18 h after the last injection, only twice daily nicotine treatment resulted in less immobility in the FST in WKY rats. Open field locomotor activity was not affected by any nicotine regimen. WKY rats had significantly less hippocampal volume (approximately 20%) than Wistar rats which was not altered by nicotine. These findings further validate the use of WKY rats as an animal model of human depression and signify the importance of inherent genetic differences in final behavioral outcome of nicotine.Progress in Neuro-Psychopharmacology and Biological Psychiatry 09/2009; 34(1):62-9. DOI:10.1016/j.pnpbp.2009.09.024 · 4.03 Impact Factor