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ABSTRACT-Effectsof tetramethylpyrazine (TMP), a major constituent of Ligusticum chuanxiong, on spatial cognitive impairment induced by permanent occlusion of bilateral common carotid arteries (2VO) and scopolamine were investigated using 8-arm radial maze performance in rats. Permanent 2VO produced a severe learning deficit in non-pretrained rats. Daily administration of TMP (3 -10 mg/kg, i.p.) from the 3rd day after permanent 2VO significantly improved the learning deficit. TMP did not influence the impairment of the retention task in the pretrained permanent 2VO rats, but it tended to reduce the number of errors elevated by 3-min delay interposition in these rats. In the scopolamine model, scopolamine (0.3 mg/kg, i.p.) significantly decreased the initial correct response and increased the number of errors. Single administration of TMP (1-3 mg/kg, i.p.) dose-dependently reversed the scopolamine-induced impairment of the maze performance. These results suggest that TMP has therapeutic potential for the treatment of dementia caused by cholinergic dysfunction and/or decrease of cerebral blood flow.Keywords: Tetramethylpyrazine, Permanent occlusion (bilateral common carotid arteries), Scopolamine, Ischemia, Learning * To whom all correspondence should be addressed .Tetramethylpyrazine (TMP) is a constituent isolatec from Ligusticum chuanxiong, which has long been usec in China as a traditional medicine to treat many patient: suffering from stroke and some cognitive impairments TMP is known to increase the cerebral blood flow (1) anc to have protective action against severe acute ischemic at. tacks, resulting in an increase of the survival rate after thf cerebral ischemia procedure in Mongolian gerbils (2) Moreover, TMP produces a vasodilatory action by inhibit ing both Ca 21 influx and intracellular Ca 2+ release (3) it dog mesenteric arterial preparation. These pharmacologi. cal profiles of TMP give rise to the possibility that it, administration may improve the cognitive impairment caused by a decrease in cerebral blood flow and/or pro. tect against the neuronal damage following cerebral ische. mia in rats.We previously reported that a chronic mild hypoper. fusion induced by permanent occlusion of bilateral common carotid arteries (2VO) caused learning deficits in thf early stage (within 1 month) and memory deficits in thf late stage (4 months after the 2VO operation) and that this progressive cognitive deficit paralleled the progress of neuronal damage (4). This animal model is advantageous for examining whether drugs prevent progressive cognitive impairment and neuronal damage induced by chronic cerebral hypoperfusion.On the other hand, it is well known that central acetylcholine (ACh) neurons play an important role in cognitive function (5, 6) and that the function of the cholinergic system can be damaged by cerebral ischemia (7 -9). In the present study, we investigated the effect of TMP on spatial cognitive impairment using two animal models: permanent 2VO-induced learning deficit and scopolamine-induced wor...