flunarizine and fonazine

KB-2796, a novel calcium channel blocker, is under development as an anti-migraine drug. We examined its effects on spreading depression (SD) in rat hippocampal slices as compared with those of flunarizine, dimetotiazine and sumatriptan. Extracellular recording was made from the CA1 subfield. An SD, followed by a series of spontaneous SDs, was induced by a brief period of hypoxia (40-60 sec). The latency of initiated SD and the interval between the initiated and subsequent spontaneous SDs were examined. KB-2796 significantly prolonged both latency and interval in a concentration-dependent manner (10(-10)-10(-8) M). KB-2796 was about 1,000 and 10 times more potent than flunarizine in prolonging the latency and interval, respectively. However, dimetotiazine and sumatriptan did not show any activity at 10(-7) and 10(-6) M. the effect of KB-2796 on SD may be due to their calcium channel blocking effects.

Topics: Animals; Calcium Channel Blockers; Cortical Spreading Depression; Flunarizine; Hippocampus; Histamine H1 Antagonists; Humans; In Vitro Techniques; Infant, Newborn; Male; Migraine Disorders; Phenothiazines; Piperazines; Rats; Rats, Sprague-Dawley; Sumatriptan

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 KCl-induced cortical spreading depression in anaesthetized rats. Cortical spreading depression was induced by application of 1 M KCl 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 H1 antagonist, failed to affect cerebral blood flow significantly. 3. After KCl 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 KCl 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 KCl application inhibited the cortical hypoperfusion that followed KCl 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 KCl 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 Ca(2+)-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.

Topics: Animals; Blood Pressure; Brain; Calcium Channel Blockers; Cerebrovascular Circulation; Cortical Spreading Depression; Flunarizine; Heart Rate; Histamine H1 Antagonists; Laser-Doppler Flowmetry; Male; Oncogene Proteins v-fos; Phenothiazines; Piperazines; Potassium Chloride; Rats; Rats, Wistar