tropisetron and Alzheimer-Disease

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Despite this, there are no drugs for preventing the onset of AD. Preclinical studies suggest that the interaction between amyloid-β peptides (Aβ) and the α7 nicotinic acetylcholine receptor (α7 nAChR) plays a key role in AD pathology, and that α7 nAChR agonists could act as potential therapeutic drugs for AD. A recent study demonstrated that tropisetron, a potent α7 nAChR agonist and serotonin 5-hydroxytryptamine3 receptor antagonist, also bound to the ectodomain of amyloid precursor protein. Furthermore, tropisetron promoted greater improvements in memory than current AD therapeutic drugs, such as memantine and donepezil. Positron emission tomography studies detected Aβ deposition and inflammation in the brains of subjects with amnestic mild cognitive impairment (MCI) before the onset of AD. Given the role of α7 nAChR in Aβ deposition and inflammation, tropisetron represents an attractive potential therapeutic drug to delay or prevent MCI and AD. Additionally as this drug is used internationally to treat chemotherapy-induced emesis, its safety record is already known.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Animals; Humans; Indoles; Inflammation; Nicotinic Agonists; Quinuclidines; Serotonin Antagonists; Thiophenes; Tropisetron

Tropisetron was identified in a screen for candidates that increase the ratio of the trophic, neurite-extending peptide sAPPα to the anti-trophic, neurite-retractive peptide Aβ, thus reversing this imbalance in Alzheimer's disease (AD). We describe here a hierarchical screening approach to identify such drug candidates, moving from cell lines to primary mouse hippocampal neuronal cultures to in vivo studies. By screening a clinical compound library in the primary assay using CHO-7W cells stably transfected with human APPwt, we identified tropisetron as a candidate that consistently increased sAPPα. Secondary assay testing in neuronal cultures from J20 (PDAPP, huAPP(Swe/Ind)) mice showed that tropisetron consistently increased the sAPPα/Aβ 1-42 ratio. In in vivo studies in J20 mice, tropisetron improved the sAPPα/Aβ ratio along with spatial and working memory in mice, and was effective both during the symptomatic, pre-plaque phase (5-6 months) and in the late plaque phase (14 months). This ameliorative effect occurred at a dose of 0.5mg/kg/d (mkd), translating to a human-equivalent dose of 5mg/day, the current dose for treatment of postoperative nausea and vomiting (PONV). Although tropisetron is a 5-HT3 receptor antagonist and an α7nAChR partial agonist, we found that it also binds to the ectodomain of APP. Direct comparison of tropisetron to the current AD therapeutics memantine (Namenda) and donepezil (Aricept), using similar doses for each, revealed that tropisetron induced greater improvements in memory and the sAPPα/Aβ1-42 ratio. The improvements observed with tropisetron in the J20 AD mouse model, and its known safety profile, suggest that it may be suitable for transition to human trials as a candidate therapeutic for mild cognitive impairment (MCI) and AD, and therefore it has been approved for testing in clinical trials beginning in 2014.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; CHO Cells; Cognition; Cricetulus; Disease Models, Animal; Hippocampus; Indoles; Mice; Mice, Inbred C57BL; Tropisetron

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

Topics: 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; Tropisetron; Tumor Necrosis Factor-alpha