Abstract
Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR α7) subtype have the potential to treat cognitive deficits in patients with Alzheimer’s disease (AD) or schizophrenia. Visuo-spatial paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR α7 agonists. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR α7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS-933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR α7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03–1 mg/kg, i.m.). These results are the first demonstration that the nAChR α7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task.
Highlights
Compounds which activate nicotinic acetylcholine receptors of the α7 receptor subtype have received considerable attention because of their potential to treat cognitive symptoms in patients with schizophrenia or Alzheimer’s disease (AD) [1, 2]
RM ANOVA confirmed the impairment of eventual accuracy with significant main effects of task difficulty (F3,21 = 139.6; nAChRa7 agonists reverse scopolamine-induced cognitive impairment in NHP CAmbridge Neuropsychological Testing Automated Battery (CANTAB) Visuo-spatial paired associates learning (vsPAL) performance p< 0.001), treatment (F4,28 = 31.3; p< 0.001) and their interaction (F12,84 = 11.1; p< 0.001)
The present study shows that treatment with the acetylcholinesterase inhibitor, donepezil or the nAChR α7 agonists, BMS-933043 or EVP-6124, improved performance of the CANTAB vsPAL task in scopolamine-treated cynomolgus monkeys
Summary
Compounds which activate nicotinic acetylcholine receptors of the α7 receptor subtype (nAChR α7) have received considerable attention because of their potential to treat cognitive symptoms in patients with schizophrenia or Alzheimer’s disease (AD) [1, 2]. With respect to AD, many studies have examined the ability of nAChR α7 agonist treatment to reverse cognitive impairment induced by administration of the nonselective muscarinic AChR antagonist scopolamine. This agent has been used extensively in rodents to model the cholinergic deficits associated with aging and AD [20, 21]. NAChR α7 agonist treatment of aged 3X Tg AD mice, at a time when subjects showed marked AD related pathology (i.e. β amyloid plaques, neuro-inflammation and neurofibrillary tangles), significantly improved spatial learning and memory in the Morris water maze task, object recognition memory and contextual fear memory demonstrating efficacy in a disease relevant model for this mechanism [26]
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