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

Rahimian, R. and Fakhfouri, G. and Mehr, S.E. and Ghia, J.-E. and Genazzani, A.A. and Payandemehr, B. and Dehpour, A.R. and Mousavizadeh, K. and Lim, D. (2013) Tropisetron attenuates amyloid-beta-induced inflammatory and apoptotic responses in rats. European Journal of Clinical Investigation, 43 (10). pp. 1039-1051.

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Abstract

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.

Item Type: Article
Additional Information: cited By 24
Uncontrolled Keywords: amyloid beta protein; calcineurin; caspase 3; cyclooxygenase 2; cytochrome c; I kappa B; inducible nitric oxide synthase; marker; tropisetron; tumor necrosis factor alpha, Alzheimer disease; animal experiment; animal model; apoptosis; article; controlled study; enzyme activity; male; maze test; neurotoxicity; nonhuman; priority journal; protein expression; protein secretion; rat, 5HT3 receptor; beta-amyloid; calcineurin; neuroinflammation; tropisetron, Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Calcineurin; Cyclooxygenase 2; Cytochromes c; Encephalitis; Hippocampus; Indoles; Male; Maze Learning; NF-kappa B; Nitric Oxide Synthase Type II; Nitrites; Rats; Rats, Wistar; Serotonin 5-HT3 Receptor Antagonists; Tumor Necrosis Factor-alpha
Subjects: QV Pharmacology
Depositing User: somayeh pourmorteza
Date Deposited: 26 May 2019 07:17
Last Modified: 26 May 2019 07:17
URI: http://eprints.iums.ac.ir/id/eprint/9644

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