Tropisetron sensitizes α7 containing nicotinic receptors to low levels of acetylcholine in vitro and improves memory-related task performance in young and aged animals
Tropisetron sensitizes α7 containing nicotinic receptors to low levels of acetylcholine in vitro and improves memory-related task performance in young and aged animals
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DOI：
10.1016/j.neuropharm.2017.02.025
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发表时间：
2017-05-01
影响因子：
4.7
通讯作者：
Terry, Alvin V., Jr.
中科院分区：
文献类型：
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作者：
Callahan, Patrick M.;Bertrand, Daniel;Terry, Alvin V., Jr.
托烷司琼是一种5-HT3受体拮抗剂，通常用于治疗化疗引起的恶心和呕吐，它也显示出高亲和力，部分激活α7烟碱型乙酰胆碱受体(A7 NAChRs)。Alpha 7 nAChRs被认为是治疗阿尔茨海默病(AD)等神经精神疾病的可行靶点。在这里，我们进一步探索了托烷司琼的nAChR药理，包括同构体α7 nAChR和最近表征的异构体α7β2 nAChR(比例为1：10)，并评估了其在幼年和老年动物中的认知效果。在非洲爪哇卵母细胞中表达的人nAChRs的电生理研究证实，托烷司琼在A7 nAChRs处具有部分激动剂活性(EC50类似于2.4µM)，在α7β2nAChRs处具有类似的作用(EC50类似于1.5muM)。此外，在持续暴露于低浓度托烷司琼(10和30 NM)时，A7和α7β2 nAChRs上由不规则脉冲的乙酰胆碱(40微米)诱发的电流增强，这表明存在“启动”或共同激动剂效应。托烷司琼(0.1-10 mg/kg)改善了年轻SD大鼠和老年Fischer大鼠的新物体识别能力。在老年雄性和雌性恒河猴中，托烷司琼(0.03-1 mg/kg)使延迟匹配的样本长延迟准确度比基线水平提高了17%，而无效剂量的多奈哌齐(0.1 mg/kg)和托烷司琼(0.03和0.1 mg/kg)联合使用使准确度改变了24%。总而言之，这些动物实验表明，托烷司琼增强认知能力，并有能力改善目前处方的AD治疗(多奈哌齐)的有效剂量范围。此外，这些效应可以通过托烷司琼对低水平的乙酰胆碱敏化含有α7的nAChRs的能力来解释。(C)2017爱思唯尔有限公司。保留所有权利。
Tropisetron, a 5-HT3 receptor antagonist commonly prescribed for chemotherapy-induced nausea and vomiting also exhibits high affinity, partial agonist activity at alpha 7 nicotinic acetylcholine receptors (a7 nAChRs). alpha 7 nAChRs are considered viable therapeutic targets for neuropsychiatric disorders such as Alzheimer's disease (AD). Here we further explored the nAChR pharmacology of tropisetron to include the homomeric alpha 7 nAChR and recently characterized heteromeric alpha 7 beta 2 nAChR (1:10 ratio) and we evaluated its cognitive effects in young and aged animals. Electrophysiological studies on human nAChRs expressed in Xenopus oocytes confirmed the partial agonist activity of tropisetron at a7 nAChRs (EC50 similar to 2.4 mu M) with a similar effect at alpha 7 beta 2 nAChRs (EC50 similar to 1.5 mu M). Moreover, currents evoked by irregular pulses of acetylcholine (40 mu M) at a7 and alpha 7 beta 2 nAChRs were enhanced during sustained exposure to low concentrations of tropisetron (10 and 30 nM) indicative of a "priming" or co-agonist effect. Tropisetron (0.1-10 mg/kg) improved novel object recognition performance in young Sprague-Dawley rats and in aged Fischer rats. In aged male and female rhesus monkeys, tropisetron (0.03-1 mg/kg) produced a 17% increase from baseline levels in delayed match to sample long delay accuracy while combination of non-effective doses of donepezil (0.1 mg/kg) and tropisetron (0.03 and 0.1 mg/kg) produced a 24% change in accuracy. Collectively, these animal experiments indicate that tropisetron enhances cognition and has the ability to improve the effective dose range of currently prescribed AD therapy (donepezil). Moreover, these effects may be explained by tropisetron's ability to sensitize alpha 7 containing nAChRs to low levels of acetylcholine. (C) 2017 Elsevier Ltd. All rights reserved.