EFFECTS OF CA2+ CHANNEL BLOCKERS ON CORTICAL HYPOPERFUSION AND EXPRESSION OF C-FOS-LIKE IMMUNOREACTIVITY AFTER CORTICAL SPREADING DEPRESSION IN RATS

1 We examined the effects of two Ca2+ channel blockers, lomerizine (KB-2796) and flunarizine, on the cortical hypoperfusion (measured by hydrogen clearance and laser Doppler flowmetry methods) and cortical c-Fos-like immunoreactivity that follow KCI-induced cortical spreading depression in anaesthetized rats. Cortical spreading depression was induced by application of 1 M KCI for 30 s to the cortical surface, 3.0 mm posterior to the area of cerebral blood flow measurement. 2 In control rats, KB-2796 (0.3 and 1 mg kg(-1), i.v.) dose-dependently increased cerebral blood flow significantly at 30 min and 15 min, respectively, after its administration. Flunarizine (1 mg kg(-1), i.v.) significantly increased cerebral blood flow 15 min after its administration. In contrast, dimetotiazine (3 mg kg(-1), i.v.), a 5-HT2 and histamine H-1 antagonist, failed to affect cerebral blood flow significantly. 3 After KCI application to the cortex, cerebral blood flow monitored by the laser Doppler flowmetry method increased transiently, for a few minutes, then fell and remained approximately 20 to 30% below control for at least 60 min, Cerebral blood flow monitored by the hydrogen clearance method was also approximately 20 to 30% below baseline for at least 60 min after KCI application. KB-2796 (0.3 and 1 mg kg(-1), i.v.) and flunarizine (1 and 3 mg kg(-1), i.v.) administered 5 min before KCI application inhibited the cortical hypoperfusion that followed KCI application, but dimetotiazine (1 and 3 mg kg(-1) i.v.) did not. 4 An indicator of neuronal activation, c-Fos-like immunoreactivity, was detected in the ipsilateral, but not in the contralateral frontoparietal cortex 2 h after KCI application. No c-Fos-like immunoreactivity was seen on either side of the brain in the hippocampus, thalamus, striatum or cerebellum. 5 KB-2796 (1 mg kg(-1), i.v.) and flunarizine (3 mg kg(-1), i.v.), but not dimetotiazine (3 mg kg(-1), i.v.), significantly attenuated the expression of c-Fos-like immunoreactivity in the ipsilateral frontoparietal cortex. 6 These findings suggest that the inhibitory effects of KB-2796 and flunarizine on the cortical hypoperfusion and expression of c-Fos-like immunoreactivity induced by spreading depression are mediated via the effects of Ca2+-entry blockade, which may include an increase in cerebral blood flow and the prevention of excessive Ca2+ influx into brain cells. KB-2796 and flunarizine may prove useful as inhibitors of cortical spreading depression in migraine.