GTS-21, a nicotinic agonist, attenuates multiple infarctions and cognitive deficit caused by permanent occlusion of bilateral common carotid arteries in rats

We examined the effects of GTS-21 [3-(2,4-dimethoxybenzylidene)-anabasein 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.