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.