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

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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 Ca2, 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.

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Abbreviations

5-HT:

5-Hydroxytryptamine

Abeta42:

Amyloid beta42

Ach:

Acetylcholine

AChE:

Acetylcholinesterase

AD:

Alzheimer’s disease

Aβ:

Amyloid-β

CB1 :

Cannabinoid type one

CGNs:

Cerebellar granule cells

CNS:

Central nervous system

COX-2:

Cyclooxygenase-2

EAE:

Experimental autoimmune encephalomyelitis

iNOS:

Inducible nitric oxide synthase

MAPK:

Mitogen-activated kinase

mCPBG:

Meta-chlorophenylbiguanide

MLA:

Methyllycaconitine citrate

MS:

Multiple sclerosis

MWM:

Morris Water Maze

NF-kB:

Nuclear factor-kappa B

OA:

Activated osteoarthritis

RA:

Rheumatoid arthritis

ROS:

Reactive oxygen species

TNF-α:

Tumor necrosis factor-alpha

α7nAchR:

Alpha7 nicotinic acetylcholine receptor

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Conflict of Interest

The authors disclose no conflicts of interest.

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Authors and Affiliations

  1. Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada

    Gohar Fakhfouri

  2. Institut Universitaire en Santé Mentale de Québec (IUSMQ) Research Center, Québec, QC, Canada

    Gohar Fakhfouri

  3. Cellular and Molecular Research Center and Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

    Kazem Mousavizadeh

  4. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P. O. Box 13145-784, Tehran, Iran

    Sharam Ejtemaei Mehr, Ahmad Reza Dehpour & Reza Rahimian

  5. Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohammad Reza Zirak

  6. Department of Immunology and Internal Medicine Section of Gastroenterology, Faculty of Medicine, University of Manitoba, Manitoba, Winnipeg, Canada

    Jean-Eric Ghia

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Correspondence to Reza Rahimian.

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Fakhfouri, G., Mousavizadeh, K., Mehr, S.E. et al. From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists. Mol Neurobiol 52, 1670–1679 (2015). https://doi.org/10.1007/s12035-014-8957-5

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