Masato Nanri (1,2,*), Jyunji Yamamoto (1), Hidekazu Miyake (1) and Hiroshi
Watanabe (2)
(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