Protective effect of GTS-21, a novel nicotinic receptor agonist, on delayed neuronal death induced by ischemia in gerbils.
The neuroprotective effects of GTS-21 [3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride] were studied and compared with those of nicotine, 9-amino-1,2,3,4-tetrahydroacridine hydrochloride hydrate (THA) and pentobarbital-Na (PB) using a cerebral ischemia model in Mongolian gerbils. The learning performance and memory retention were elucidated by a step-through passive avoidance task at 2 and 3 days after ischemia-reperfusion. In this task, the ischemia-operated gerbils showed impairment of learning performance and memory retention. Neuronal cell death in the hippocampal CA1 area was observed at 7 days after ischemia. When administered i.p. 30 min before ischemia, GTS-21 (5 mg/kg), (-)-nicotine (1.5 mg/kg), THA (5 mg/kg) and PB (50 mg/kg) significantly attenuated the impairment of passive avoidance performance and the neuronal cell death induced by the ischemia. When administered orally twice daily for 2 weeks prior to the ischemia, GTS-21 (10 mg/kg) significantly suppressed both amnesia and neuronal cell death, while (-)-nicotine (10 mg/kg) and THA (10 mg/kg) suppressed only the amnesia. These results suggest that GTS-21 exerts a protective activity on not only impairment of learning and memory but also delayed neuronal death and that the underlying mechanism of GTS-21 differs from that of nicotine or THA.
Nanri
M
M
Department of Pharmacology, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Yamamoto
J
J
Miyake
H
H
Watanabe
H
H
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D018757:GABA Modulators / Q000494:pharmacology; D005849:Gerbillinae; D008297:Male; D008568:Memory / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010424:Pentobarbital / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D013619:Tacrine / Q000031:analogs & derivatives / Q000494:pharmacology
D001597:Benzylidene Compounds; D018757:GABA Modulators; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D011725:Pyridines; D013619:Tacrine; D009538:Nicotine; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D010424:Pentobarbital