Beyond the 5-HT3 receptors: A role for α7nACh receptors in neuroprotective aspects of tropisetron.
Accumulation of reactive oxygen species, such as hydrogen peroxide (H2O2), generated by inflammatory cells or other pathological conditions, leads to oxidative stress, which may contribute to the neuronal degeneration observed in a wide variety of neurodegenerative disorders such as Alzheimer's disease. Recent investigations have described effective properties of tropisetron, such as antiphlogistic action or protection against β-amyloid induced-neuroinflammation in rats. Our data revealed that H2O2-induced cell death in rat pheochromocytoma cell line (PC12) can be inhibited by tropisetron, as defined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay, caspase 3 and caspase 12 levels. We further showed that tropisetron exerts its protective effects by upregulation of heme oxygenase-1, glutathione, catalase activity, and nuclear factor-erythroid 2 p45-related factor 2 level. Moreover, tropisetron was recently found to be a partial agonist of α7 nicotinic acetylcholine receptor (α7nAChR). The activation of α7nAChR could inhibit inflammatory and apoptotic signaling pathways in the oxidative stress conditions. In this study, selective α7nAChR antagonists (methyllycaconitine) reversed the effects of tropisetron on caspase 3 level. Our findings indicated that tropisetron can protect PC12 cells against H2O2-induced neurotoxicity through α7nAChR in vitro.
Department of Animal Physiology, Faculty of Biology, Kharazmi University, Tehran, Islamic Republic of Iran.
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Khalifeh
Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec City, Québec, Canada. Institut universitaire en santé mentale de Québec, Québec City, Québec, Canada Institut Universitaire en Sante Mentale de Quebec (IUSMQ) research center, Quebec, Canada.
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Fakhfouri
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
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Mehr
Cellular and Molecular Research Center and Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Mousavizadeh
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
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Dehpour
NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran.
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Khodagholi
Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Islamic Republic of Iran.
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Kazmi
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran rahimian78@gmail.com.
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Rahimian
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018679:Cholinergic Agonists / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D007211:Indoles / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology*; D000077526:Tropisetron; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects*
D000975:Antioxidants; D018679:Cholinergic Agonists; D007211:Indoles; D018696:Neuroprotective Agents; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077526:Tropisetron; D006861:Hydrogen Peroxide; D020169:Caspases
5-HT3 receptor; PC12; Tropisetron; oxidative stress; α7nAChR