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

Background Alzheimer's disease (AD) is a neurodegenerative disorder featured by deposition of beta-amyloid (Ab) 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 (Ab) 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 Ab 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 Ab 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 Ab-induced injury. Conclusion Our findings indicate that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT₃ receptor-dependent and independent pathways. copy; 2013 Stichting European Society for Clinical Investigation Journal Foundation.