Effect of NS-7 on cerebral blood flow, brain tissue metabolism, and expression of immediate early genes after experimental cerebral ischemia in SHR

The effects of NS-7 [4-(4-fluorophenyl)-2-methyl-6- (5-piperidinopentyloxy) pyrimidine hydrochloride], a neuroprotective agent for the treatment at the acute phase of cerebrovascular diseases, on the changes in the brain energy metabolism, brain concentrations of monoamines and amino acids, and mRNA levels for immediate early genes, induced by the bilateral ligation of the common carotid arteries (BCL) were investigated in spontaneously hypertensive rats (SHR). BCL for 1 hr caused a marked decrease in ATP and glucose contents with a concomitant increase in lactate level in the supratentorial brain tissue. The brain con-tents of amino acids were also changed. In addition, mRNA for Egr-1 was elevated, while that for CREB was substantially but not significantly lowered after cerebral ischemia. NS-7 (0.25 mg/kg, i.v.), when administered at 40 min after the start of BCL, significantly reversed the ischemia-induced decreases in the cerebral glucose and ATP contents. Moreover, NS-7 restored the ischemia-induced reduction in CREB mRNA. On the other hand, NS-7 exerted no influence on various physiological parameters including blood pressure, heart rate and cerebral blood flow. These findings suggest that NS-7 may achieve its cerebroprotective action by reversing the ischemic breakdown of the cerebral energy metabolism, and thereby possibly improving the loss of cellu-lar CREB signals.