AMELIORATIVE EFFECTS OF THE CENTRALLY ACTIVE CHOLINESTERASE INHIBITOR, NIK-247, ON IMPAIRMENT OF WORKING MEMORY IN RATS

Using a three-panel runway task, the effects of NIK-247 on impairment of working memory produced by scopolamine, hippocampal lesions, and cerebral ischemia were investigated in rats; these effects were compared with those of the well-known cholinesterase inhibitors, tetrahydroaminoacridine (THA) and physostigmine. Intraperitoneal injection of scopolamine (0.56 mg/kg) significantly increased the number of errors (pushes made on the two incorrect panels of the three-panel gates located at four choice points). NIK-247 (3.2-18 mg/kg PO), THA (1-10 mg/kg PO), and physostigmine (0.1 and 0.32 mg/kg IP) dose-dependently reduced the increase in errors induced by scopolamine. NIK-247 (32 mg/kg) was also effective in reducing the increase in errors produced by lesions of the dorsal hippocampus. A 5-min period of cerebral ischemia markedly increased the number of errors. NIK-247 (3.2 and 10 mg/kg), given immediately after blood flow recirculation and again 20 min before the runway test carried out 24 h after ischemia, significantly reduced the increase in errors expected to occur after ischemia. Tetrahydroaminoacridine (3.2 mg/kg) and physostigmine (0.1 mg/kg) similarly reversed the increased errors in ischemic rats. These results suggest that NIK-247 alleviates the impairment of working memory produced by scopolamine, hippocampal lesions, and cerebral ischemia, possibly through activation of the central cholinergic system.