Ondansetron, a carbazole derivative, is a competitive and selective antagonist of serotonin 5-HT3 receptors with an IC50 value of 103pM[1]. Ondansetron inhibits the mobilization of intracellular Ca2+, the production of thromboxane B2, and the release of ATP by weakening the IP3 signaling pathway and the MAPK (p38 and ERK2) pathway, which prevents platelet aggregation[2]. Ondansetron has been widely used as an antiemetic for cancer treatment-induced and anesthesia-related nausea and vomiting[3].
In vitro, Ondansetron incubation (1µM) for 4 hours significantly reduced the 1µg/ml lipopolysaccharide (LPS)-stimulated production of inflammatory factors (IL-6, IL-1β, TNF-α) and the chemokine receptor CXCR4 in rat neutrophils[4]. Treatment with 10µM Ondansetron for 3 minutes reduced the activity of the excitatory amino acid transporter 3 (EAAT3) expressed in Xenopus oocytes[5]. Treatment with 10µM Ondansetron for 24 hours increased the secretion of apolipoprotein E (apoE) in mouse astrocytes and elevated the levels of ABCA1 mRNA and protein[6].
In vivo, Ondansetron treatment via intraperitoneal injection at a dose of 1.5mg/kg/day for 6 days increased the survival time of mice infected with Enterovirus 71 and reduced the viral load in various tissues[7]. Daily intraperitoneal injection of Ondansetron (2mg/kg) for 6 days alleviated the trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats and reduced the levels of inflammatory cytokines in the colon[8]. Intraperitoneal injection of Ondansetron (1mg/kg/day) for 5 days improved the cognitive function of epileptic rats, attenuated hippocampal impairment, stabilized the synaptic cytoskeleton structure of the hippocampus, and regulated plasticity[9].
References:
[1] Brown A M, Hope A G, Lambert J J, et al. Ion permeation and conduction in a human recombinant 5-HT3 receptor subunit (h5-HT3A)[J]. The Journal of Physiology, 1998, 507(Pt 3): 653.
[2] Liu F C, Liou J T, Liao H R, et al. The anti-aggregation effects of ondansetron on platelets involve IP3 signaling and MAP kinase pathway, but not 5-HT3-dependent pathway[J]. Thrombosis Research, 2012, 130(3): e84-e94.
[3] Ye J H, Ponnudurai R, Schaefer R. Ondansetron: a selective 5‐HT3 receptor antagonist and its applications in CNS‐related disorders[J]. CNS drug reviews, 2001, 7(2): 199-213.
[4] Tao L, Zhang Z, Li C, et al. The therapeutic targets and signaling mechanisms of ondansetron in the treatment of critical illness in the ICU[J]. Frontiers in Pharmacology, 2024, 15: 1443169.
[5] Hur W, Lee M K, Park H P, et al. Ondansetron attenuates the activity of excitatory amino acid transporter type 3 expressed in Xenopus oocytes[J]. European Journal of Pharmacology, 2014, 733: 7-12.
[6] Shinohara M, Shinohara M, Zhao J, et al. 5-HT3 antagonist ondansetron increases apoE secretion by modulating the LXR-ABCA1 pathway[J]. International journal of molecular sciences, 2019, 20(6): 1488.
[7] Li Z, Rui J, Li J, et al. Ondansetron exhibits potent antiviral activity against enterovirus 71 infection in vitro and in vivo[J]. Virus Research, 2026: 199771.
[8] Motavallian-Naeini A, Minaiyan M, Rabbani M, et al. Anti-inflammatory effect of ondansetron through 5-HT3 receptors on TNBS-induced colitis in rat[J]. EXCLI journal, 2012, 11: 30.
[9] Zhang Y, Sun Y, Gao J, et al. Ondansetron reduces seizures and improves cognitive impairment in a rat model of temporal lobe epilepsy[J]. IBRO Neuroscience Reports, 2025.