Tropisetron attenuates amyloid-beta-induced inflammatory and apoptotic responses in rats

Eur J Clin Invest. 2013 Oct;43(10):1039-51. doi: 10.1111/eci.12141. Epub 2013 Aug 13.


Background: Alzheimer's disease (AD) is a neurodegenerative disorder featured by deposition of beta-amyloid (Aβ) plaques in the hippocampus and associated cortices and progressive cognitive decline. Tropisetron, a selective 5-HT3 receptor antagonist, is conventionally used to counteract chemotherapy-induced emesis. Recent investigations describe antiphlogistic properties for tropisetron. It has been shown that tropisetron protects against rat embolic stroke. We investigated protective properties of tropisetron in a beta-amyloid (Aβ) rat model of AD and possible involvement of 5-HT3 receptors.

Material and methods: Aβ (1-42) was injected into the hippocampus of male rats. Animals were treated intracerebroventricularly with tropisetron, mCPBG (selective 5-HT3 receptor agonist) or mCPBG plus tropisetron on days 1, 3, 5 and 7. Seven days following Aβ administration, inflammatory markers (TNF-α, COX-2, iNOS and NF-κB), apoptotic markers (caspase 3 cytochrome c release) and calcineurin phosphatase activity were assessed in hippocampus.

Results: Seven days following Aβ inoculation, control animals displayed dramatic increase in TNF-α, COX-2, iNOS, NF-κB, active caspase 3, cytochrome c release and calcineurin phosphatase activity in the hippocampus. Tropisetron significantly diminished the elevated levels of these markers and reversed the cognitive deficit. Interestingly, tropisetron was also found to be a potent inhibitor of calcineurin phosphatase activity. The selective 5-HT3 receptor agonist mCPBG, when co-administered with tropisetron, completely reversed the procognitive and anti-apoptotic properties of tropisetron while it could only partially counteract the anti-inflammatory effects. mCPBG alone significantly aggravated Aβ-induced injury.

Conclusion: Our findings indicate that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and independent pathways.

Keywords: 5HT3 receptor; beta-amyloid; calcineurin; neuroinflammation; tropisetron.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Apoptosis / drug effects*
  • Calcineurin / drug effects
  • Cyclooxygenase 2 / metabolism
  • Cytochromes c / metabolism
  • Encephalitis / drug therapy
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Indoles / pharmacology*
  • Male
  • Maze Learning / drug effects
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Nitrites / metabolism
  • Rats
  • Rats, Wistar
  • Serotonin 5-HT3 Receptor Antagonists / pharmacology*
  • Tropisetron
  • Tumor Necrosis Factor-alpha / metabolism


  • Amyloid beta-Peptides
  • Indoles
  • NF-kappa B
  • Nitrites
  • Serotonin 5-HT3 Receptor Antagonists
  • Tumor Necrosis Factor-alpha
  • Tropisetron
  • Cytochromes c
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Cyclooxygenase 2
  • Calcineurin