From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists.
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.
Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada.|Institut Universitaire en Santé Mentale de Québec (IUSMQ) Research Center, Québec, QC, Canada.
Gohar
G
Fakhfouri
Cellular and Molecular Research Center and Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
Kazem
K
Mousavizadeh
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P. O. Box 13145-784, Tehran, Iran.
Sharam Ejtemaei
SE
Mehr
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P. O. Box 13145-784, Tehran, Iran.
Ahmad Reza
AR
Dehpour
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Mohammad Reza
MR
Zirak
Department of Immunology and Internal Medicine Section of Gastroenterology, Faculty of Medicine, University of Manitoba, Manitoba, Winnipeg, Canada.
Jean-Eric
JE
Ghia
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P. O. Box 13145-784, Tehran, Iran. rahimian78@gmail.com.
Reza
R
Rahimian
D000818:Animals; D004358:Drug Therapy / Q000379:methods; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000188:drug therapy*; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000627:therapeutic use*; D000077526:Tropisetron; D014839:Vomiting / Q000188:drug therapy*
D007211:Indoles; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D000077526:Tropisetron
5-HT3 receptor antagonist; Anti-inflammatory; Neurodegeneration; Neuroinflammation; Neuroprotective