title: Tropisetron sensitizes α7 containing nicotinic receptors to low levels of acetylcholine in vitro and improves memory-related task performance in young and aged animals.
abstract: Tropisetron, a 5-HT3receptor antagonist commonly prescribed for chemotherapy-induced nausea and vomiting also exhibits high affinity, partial agonist activity at α7 nicotinic acetylcholine receptors (α7 nAChRs). α7 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 α7 nAChR and recently characterized heteromeric α7β2 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 α7 nAChRs (EC50∼2.4 μM) with a similar effect at α7β2 nAChRs (EC50∼1.5 μM). Moreover, currents evoked by irregular pulses of acetylcholine (40 μM) at α7 and α7β2 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 α7 containing nAChRs to low levels of acetylcholine.
authors.affiliation: Department of Pharmacology and Toxicology, Augusta University, Augusta, GA 30912, United States. Electronic address: pcallahan@augusta.edu.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Callahan
authors.affiliation: HiQScreen Sàrl, 6, rte de Compois, 1222 Vésenaz, Geneva, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.affiliation: HiQScreen Sàrl, 6, rte de Compois, 1222 Vésenaz, Geneva, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.affiliation: Department of Pharmacology and Toxicology, Augusta University, Augusta, GA 30912, United States.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Plagenhoef
authors.affiliation: Department of Pharmacology and Toxicology, Augusta University, Augusta, GA 30912, United States.
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000375:Aging / Q000187:drug effects / Q000378:metabolism / Q000523:psychology; D000818:Animals; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007189:Indans / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D009865:Oocytes; D010880:Piperidines / Q000494:pharmacology; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology; D000077526:Tropisetron; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D007189:Indans; D007211:Indoles; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D010880:Piperidines; D012702:Serotonin Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077526:Tropisetron; D000077265:Donepezil; D000109:Acetylcholine
keywords: Aging; Alzheimer's disease; Cognition; Non-human primate; Rat; Xenopus oocytes