Effect of KC-404 on experimental cerebral infarction in rats

Abstract

Experimental cerebral infarction accompanying altered cerebral energy metabolism and cerebral edema was produced in rats by injecting arachidonate into the left carotid artery. In the present study, the effects of 3-isobutyryl-2-isopropylpyrazolo[1, 5-α]pyridine (KC-404) on these ischemic insults as well as on the regional cerebral blood flow (r-CBF) were studied. 1) Cerebral metabolism: On the 7th day of infarction, a significant decrease in ATP content and an increase in glucose content were observed, especially in the left hemisphere. There were no significant changes in lactate and puruvate contents as compared with normal rat brain. Treatment with KC-404 (10 mg/kg, p.o.) once on the 7th day or twice on the 6th and 7th days of infarction caused a significant increase in ATP content and a decrease in lactate content. Increased content of glucose tended to be suppressed by KC-404. In normal rats, KC-404 (10 mg/kg, p.o.) caused slight but significant increases in cerebral ATP, glucose and pyruvate contents. 2) Cerebral edema: On the 4th day of infarction, significant increases in water content and Na⁺/K⁺ ratio and a decrease in K⁺ content were observed in the left hemisphere. Treatment with KC-404 (10 mg/kg, p.o.) for three preceding days showed a significant suppression of increased water content with a tendency to improve altered electrolyte levels. 3) r-CBF: KC-404 (0.05 mg/kg/min) infused i.v. for 15 min increased more markedly the r-CBF in the affected left hemisphere as compared with that in normal brain. These results show that KC-404 exerts therapeutic effects on altered cerebral metabolism and cerebral edema in rats with arachidonate-induced cerebral infarction when administered during the restitution period of the lesion. Furthermore, it is suggested that enhancement of cerebral blood flow in the affected hemisphere would contribute, at least partly, to these observed effects of KC-404.