Beyond the 5-HT3 receptors: A role for α7nACh receptors in neuroprotective aspects of tropisetron

Hum Exp Toxicol. 2015 Sep;34(9):922-31. doi: 10.1177/0960327114562034.

Abstract

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.

Keywords: 5-HT3 receptor; PC12; Tropisetron; oxidative stress; α7nAChR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Cholinergic Agonists / pharmacology*
  • Hydrogen Peroxide / toxicity
  • Indoles / pharmacology*
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects
  • PC12 Cells
  • Rats
  • Receptors, Serotonin, 5-HT3 / drug effects*
  • Serotonin 5-HT3 Receptor Antagonists / pharmacology*
  • Tropisetron
  • alpha7 Nicotinic Acetylcholine Receptor / drug effects*

Substances

  • Antioxidants
  • Cholinergic Agonists
  • Indoles
  • Neuroprotective Agents
  • Receptors, Serotonin, 5-HT3
  • Serotonin 5-HT3 Receptor Antagonists
  • alpha7 Nicotinic Acetylcholine Receptor
  • Tropisetron
  • Hydrogen Peroxide
  • Caspases