The multi-functional drug tropisetron binds APP and normalizes cognition in a murine Alzheimer's model

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• 作者：Patricia Spilman ; Olivier Descamps ; Olivia Gorostiza ; Clare Peters-Libeu ; Karen S. Poksay ; Alex ; er Matalis ; Jesus Campagna ; Alex ; er Patent ; Rammohan Rao ; Varghese John ; Dale E. Bredesen
• 关键词：AD ; Alzheimer's disease ; APP ; amyloid precursor protein ; A尾 ; amyloid beta ; sAPP伪 ; soluble amyloid precursor protein alpha ; sAPP尾 ; soluble amyloid precursor protein beta ; CHO7W ; Chinese hamster ovary cells stably transfected with human APP wildtype ; 伪7nAChR ; alpha 7 nicotinic acetylcholine receptor ; 5-HT3 ; 5-hydroxytryptophan 3 (receptor) ; GABA ; gamma-aminobutyic acid ; PONV ; post-operative nausea and vomiting ; MCI ; mild cognitive impairment ; BACE ; beta-site APP cleaving enzyme ; Jcasp ; juxtame
• 刊名：Brain Research
• 出版年：10 March, 2014
• 年：2014
• 卷：1551
• 期：Complete
• 页码：25-44
• 全文大小：3578 K

文摘

Tropisetron was identified in a screen for candidates that increase the ratio of the trophic, neurite-extending peptide sAPP伪 to the anti-trophic, neurite-retractive peptide A尾, 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 sAPP伪. Secondary assay testing in neuronal cultures from J20 (PDAPP, huAPP^Swe/Ind) mice showed that tropisetron consistently increased the sAPP伪/A尾 1-42 ratio. In in vivo studies in J20 mice, tropisetron improved the sAPP伪/A尾 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 0.5 mg/kg/d (mkd), translating to a human-equivalent dose of 5 mg/day, the current dose for treatment of postoperative nausea and vomiting (PONV). Although tropisetron is a 5-HT₃ receptor antagonist and an 伪₇nAChR 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 sAPP伪/A尾1-42 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.