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 (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.


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.


CONCLUSIONS
Our findings indicate that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and independent pathways.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Injury Repair Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Reza
R
Rahimian
Gohar
G
Fakhfouri
Shahram
S
Ejtemaei Mehr
Jean-Eric
JE
Ghia
Armando A
AA
Genazzani
Borna
B
Payandemehr
Ahmad Reza
AR
Dehpour
Kazem
K
Mousavizadeh
Dmitry
D
Lim
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019703:Calcineurin / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology*; D000077526:Tropisetron; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016229:Amyloid beta-Peptides; D007211:Indoles; D016328:NF-kappa B; D009573:Nitrites; D058831:Serotonin 5-HT3 Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D000077526:Tropisetron; D045304:Cytochromes c; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D019703:Calcineurin
5HT3 receptor; beta-amyloid; calcineurin; neuroinflammation; tropisetron