Masato Nanri (1,2,*), Hidekazu Miyake (1), Yukihisa Murakami (2), Kinzo
Matsumoto (2) and Hiroshi Watanabe (2)
(1) Section of Pharmacology Research Laboratory, Taiho Pharmaceutical
Co., Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0132, Japan
(2) Department of Pharmacology, Research Institute for Wakan-Yaku (Oriental
Medicines), Toyama Medical and Pharmaceutical University, 2630 Sugitani,
Toyama 930-0194, Japan
(*) To whom correspondence should be addressed (1).
Abstract: We examined the effects of GTS-21 [3-(2,4-dimethoxybenzylidene)-anabaseine
dihydrochloride], a nicotinic agonist, on histopathological changes of the
brain and radial maze learning performance in rats with permanent occlusion
of the bilateral common carotid arteries (2VO) and elucidated whether this
compound has a protective effect against the neuronal degeneration and spatial
cognitive deficit caused by chronic ischemia. Rats were administered GTS-21
(1 and 10 mg/kg, p.o.) or vehicle 24 hr and 30 min before the 2VO operation
and then once daily for 2 months after the operation. The 2VO rats given
vehicle had multiple infarctions in the cerebral cortex, hippocampus and
striatum and rarefaction in the white matter at 2 months after the operation,
although the number and distribution of infarctions varied among individual
animals. In addition, the 2VO rats given vehicle showed a higher rate of
errors in the acquisition trials of the 8-arm radial maze task than sham-operated
controls. However, 2VO rats treated with GTS-21 (1 and 10 mg/kg, p.o.) showed
significantly decreased neuropathological changes and less errors in the
acquisition trials compared to the vehicle-treated 2VO rats. These results
indicate that GTS-21 attenuates impairment of spatial cognitive deficit
and progressive neuronal degeneration induced by 2VO and suggest that this
compound is beneficial for the treatment of neurodegenerative diseases following
chronic cerebral hypoperfusion.
Keywords: GTS-21, Nicotinic agonist, Cerebral ischemia, Multiple infarction,
Hypoperfusion