Tropisetron attenuates amyloid‐beta‐induced inflammatory and apoptotic responses in rats. (13th August 2013)

• Record Type: Journal Article
• Authors: Rahimian, Reza; Fakhfouri, Gohar; Ejtemaei Mehr, Shahram; Ghia, Jean‐Eric; Genazzani, Armando A.; Payandemehr, Borna; Dehpour, Ahmad Reza; Mousavizadeh, Kazem; Lim, Dmitry
• Is Part Of: European journal of clinical investigation. Volume 43:Number 10(2013:Oct.)
• Page Start: 1039
• Page End: 1051
• Publication Date: 2013-08-13
• Subjects: Pathology -- Periodicals; Medical research -- Periodicals; 616.075
• DOI: 10.1111/eci.12141
• Languages: English
• ISSNs: 0014-2972

Abstract

<abstract abstract-type="main" id="eci12141-abs-0001"> <title>Abstract</title> <sec id="eci12141-sec-0001" sec-type="section"> <title>Background</title> <p>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‐HT<sub>3</sub> 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‐HT<sub>3</sub> receptors.</p> </sec> <sec id="eci12141-sec-0002" sec-type="section"> <title>Material and methods</title> <p>Aβ (1–42) was injected into the hippocampus of male rats. Animals were treated intracerebroventricularly with tropisetron, mCPBG (selective 5‐HT<sub>3</sub> 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 <italic>c</italic> release) and calcineurin phosphatase activity were assessed in hippocampus.</p> </sec> <sec id="eci12141-sec-0003" sec-type="section"> <title>Results</title> <p>Seven days following Aβ inoculation, control animals displayed dramatic increase in TNF‐α, COX‐2, iNOS, NF‐κB, active caspase 3, cytochrome <italic>c</italic> 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‐HT<sub>3</sub> 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.</p> </sec> <sec id="eci12141-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Our findings indicate that tropisetron protects against Aβ‐induced neurotoxicity <italic>in vivo</italic> through both 5‐HT<sub>3</sub> receptor‐dependent and independent pathways.</p> </sec> </abstract>