Combination of a novel antidementia drug FK960 with donepezil synergistically improves memory deficits in rats

Abstract

FK960 [ N-(4-acetyl-1-piperazinyl)- p-fluorobenzamide monohydrate] is a novel antidementia drug which has been demonstrated to have potential cognitive-improving actions through enhancement of somatostatin release. Since the mechanism of action is different from cholinesterase inhibitors (CEIs), FK960 might be more efficacious at alleviating cognitive deficiencies than CEIs alone, particularly when used in combination therapies with CEIs. We examined the ability of FK960 and donepezil, a CEI, to improve memory deficits in three rat models of dementia: scopolamine-treated rats, rats received with bilateral nucleus basalis magnocellularis (NBM) lesions, and aged rats using the passive avoidance task. FK960 (0.1–10 mg/kg ip) significantly ameliorated the memory deficits in all three models. Donepezil (0.032–3.2 mg/kg ip) significantly improved the deficits induced by both scopolamine or by NBM lesion, but no significant effect was observed in the aged rat model. To determine whether concomitant treatment would be more effective, we coadministered FK960 and donepezil in NBM-lesioned rats using the same task. Concurrent administration of FK960 and donepezil at dosages that were suboptimal when the compounds were administered alone (FK960, 0.1 mg/kg; donepezil, 0.1 mg/kg) significantly improved memory impairment in the animals. Furthermore, coadministration of FK960 and donepezil at optimal dosages for both (FK960, 1 mg/kg; donepezil, 0.32 mg/kg) produced marked amelioration of memory deficits that was more efficacious than when either compound was administered individually. These results demonstrate that FK960 is more efficacious than CEIs in improving memory deficits, and that FK960 has synergistic efficacy when combined with CEIs.