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.
Yamamoto
T
T
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Ohno
M
M
Kitajima
I
I
Yatsugi
S
S
Ueki
S
S
D000110:Acetylcholinesterase / Q000502:physiology; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D002800:Cholinesterase Inhibitors; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D011939:Mental Recall / Q000187:drug effects* / Q000502:physiology; D009949:Orientation / Q000187:drug effects / Q000502:physiology; D010830:Physostigmine / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012153:Retention, Psychology / Q000187:drug effects / Q000502:physiology; D012601:Scopolamine / Q000494:pharmacology; D013619:Tacrine / Q000494:pharmacology
D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D011619:Psychotropic Drugs; D011950:Receptors, Cholinergic; D013619:Tacrine; D010830:Physostigmine; C049860:amiridine; D012601:Scopolamine; D000110:Acetylcholinesterase