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From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists.

Abstract
5-HT3 receptor antagonists are extensively used as efficacious agents in counteracting chemotherapy-induced emesis. Recent investigations have shed light on other potential effects (analgesic, anxiolytic, and anti-psychotic). Some studies have reported neuroprotective properties for the 5-HT3 receptor antagonists in vitro and in vivo. When administered to Aβ-challenged rat cortical neurons, 5-HT3 receptor antagonists substantially abated apoptosis, elevation of cytosolic Ca(2), glutamate release, reactive oxygen species (ROS) generation, and caspase-3 activity. In addition, in vivo studies show that 5-HT3 receptor antagonists possess, alongside their anti-emetic effects, notable immunomodulatory properties in CNS. We found that pretreatment with tropisetron significantly improved neurological deficits and diminished leukocyte transmigration into the brain, TNF-α level, and brain infarction in a murine model of embolic stroke. Our recent investigation revealed that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and -independent pathways. Tropisetron, in vitro, was found to be an efficacious inhibitor of the signaling pathway leading to the activation of pro-inflammatory NF-κB, a transcription factor pivotal to the upregulation of several neuroinflammatory mediators in brain. This mini review summarizes novel evidence concerning effects of 5-HT3 antagonists and their possible mechanisms of action in ameliorating neurodegenerative diseases including Alzheimer, multiple sclerosis, and stroke. Further, we discuss some newly synthesized 5-HT3 receptor antagonists with dual properties of 5-HT3 receptor blockade/alpha-7 nicotinic receptor activator and their potential in management of memory impairment. Since 5-HT3 receptor antagonists possess a large therapeutic window, they can constitute a scaffold for design and synthesis of new neuroprotective medications.
AuthorsGohar Fakhfouri, Kazem Mousavizadeh, Sharam Ejtemaei Mehr, Ahmad Reza Dehpour, Mohammad Reza Zirak, Jean-Eric Ghia, Reza Rahimian
JournalMolecular neurobiology (Mol Neurobiol) Vol. 52 Issue 3 Pg. 1670-1679 (Dec 2015) ISSN: 1559-1182 [Electronic] United States
PMID25377794 (Publication Type: Journal Article, Review)
Chemical References
  • Indoles
  • Receptors, Serotonin, 5-HT3
  • Serotonin 5-HT3 Receptor Antagonists
  • Tropisetron
Topics
  • Animals
  • Drug Therapy (methods)
  • Humans
  • Indoles (therapeutic use)
  • Multiple Sclerosis (drug therapy)
  • Receptors, Serotonin, 5-HT3 (drug effects)
  • Serotonin 5-HT3 Receptor Antagonists (therapeutic use)
  • Tropisetron
  • Vomiting (drug therapy)

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