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Effects of Ca 2+ channel blockers on cortical hypoperfusion and expression of c‐Fos‐like immunoreactivity after cortical spreading depression in rats
Author(s) -
Shimazawa Masamitsu,
Hara Hideaki,
Watano Tomokazu,
Sukamoto Takayuki
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb16624.x
Subject(s) - cortical spreading depression , flunarizine , cerebral blood flow , cerebral cortex , perfusion , chemistry , blood flow , medicine , hemodynamics , anesthesia , cortex (anatomy) , endocrinology , biology , calcium , neuroscience , migraine
1 We examined the effects of two Ca 2+ 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 KC1 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‐HT 2 and histamine H 1 antagonist, failed to affect cerebral blood flow significantly. 3 After KC1 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 KC1 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 KC1 application inhibited the cortical hypoperfusion that followed KC1 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 KC1 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 Ca 2+ influx into brain cells. KB‐2796 and flunarizine may prove useful as inhibitors of cortical spreading depression in migraine.