Masato Nanri (1,2,*), Jyunji Yamamoto (1), Hidekazu Miyake (1) and Hiroshi
(1) Department of Pharmacology, Taiho Pharmaceutical Co., Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-01, Japan
(2) Department of Pharmacology, Research Institute for Wakan-Yaku (Oriental Medicines), Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan
(*) To whom correspondence should be addressed (1).
Abstract: 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.
Keywords: GTS-21, THA, Ischemia, Mongolian gerbil, Nicotinic agonist