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. 1995 Aug;115(8):1359–1368. doi: 10.1111/j.1476-5381.1995.tb16624.x

Effects of Ca2+ channel blockers on cortical hypoperfusion and expression of c-Fos-like immunoreactivity after cortical spreading depression in rats.

M Shimazawa 1, H Hara 1, T Watano 1, T Sukamoto 1
PMCID: PMC1908864  PMID: 8564192

Abstract

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.

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Selected References

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  1. AUKLAND K., BOWER B. F., BERLINER R. W. MEASUREMENT OF LOCAL BLOOD FLOW WITH HYDROGEN GAS. Circ Res. 1964 Feb;14:164–187. doi: 10.1161/01.res.14.2.164. [DOI] [PubMed] [Google Scholar]
  2. Akaike N., Ishibashi H., Hara H., Oyama Y., Ueha T. Effect of KB-2796, a new diphenylpiperazine Ca2+ antagonist, on voltage-dependent Ca2+ currents and oxidative metabolism in dissociated mammalian CNS neurons. Brain Res. 1993 Aug 13;619(1-2):263–270. doi: 10.1016/0006-8993(93)91620-8. [DOI] [PubMed] [Google Scholar]
  3. Duckrow R. B. A brief hypoperfusion precedes spreading depression if nitric oxide synthesis is inhibited. Brain Res. 1993 Aug 6;618(2):190–195. doi: 10.1016/0006-8993(93)91265-t. [DOI] [PubMed] [Google Scholar]
  4. Duckrow R. B. Regional cerebral blood flow during spreading cortical depression in conscious rats. J Cereb Blood Flow Metab. 1991 Jan;11(1):150–154. doi: 10.1038/jcbfm.1991.18. [DOI] [PubMed] [Google Scholar]
  5. Ehret G., Fischer R. Neuronal activity and tonotopy in the auditory system visualized by c-fos gene expression. Brain Res. 1991 Dec 20;567(2):350–354. doi: 10.1016/0006-8993(91)90819-h. [DOI] [PubMed] [Google Scholar]
  6. Fabricius M., Jensen L. H., Lauritzen M. Microdialysis of interstitial amino acids during spreading depression and anoxic depolarization in rat neocortex. Brain Res. 1993 May 28;612(1-2):61–69. doi: 10.1016/0006-8993(93)91644-8. [DOI] [PubMed] [Google Scholar]
  7. Hall E. D., Smith S. L. The 21-aminosteroid antioxidant tirilazad mesylate, U-74006F, blocks cortical hypoperfusion following spreading depression. Brain Res. 1991 Jul 12;553(2):243–248. doi: 10.1016/0006-8993(91)90832-g. [DOI] [PubMed] [Google Scholar]
  8. Hansen A. J., Zeuthen T. Extracellular ion concentrations during spreading depression and ischemia in the rat brain cortex. Acta Physiol Scand. 1981 Dec;113(4):437–445. doi: 10.1111/j.1748-1716.1981.tb06920.x. [DOI] [PubMed] [Google Scholar]
  9. Hara H., Harada K., Sukamoto T. Chronological atrophy after transient middle cerebral artery occlusion in rats. Brain Res. 1993 Aug 6;618(2):251–260. doi: 10.1016/0006-8993(93)91273-u. [DOI] [PubMed] [Google Scholar]
  10. Hara H., Ozaki A., Yoshidomi M., Sukamoto T. Protective effect of KB-2796, a new calcium antagonist, in cerebral hypoxia and ischemia. Arch Int Pharmacodyn Ther. 1990 Mar-Apr;304:206–218. [PubMed] [Google Scholar]
  11. Hara H., Yokota K., Shimazawa M., Sukamoto T. Effect of KB-2796, a new diphenylpiperazine Ca2+ antagonist, on glutamate-induced neurotoxicity in rat hippocampal primary cell cultures. Jpn J Pharmacol. 1993 Apr;61(4):361–365. doi: 10.1254/jjp.61.361. [DOI] [PubMed] [Google Scholar]
  12. Herrera D. G., Maysinger D., Gadient R., Boeckh C., Otten U., Cuello A. C. Spreading depression induces c-fos-like immunoreactivity and NGF mRNA in the rat cerebral cortex. Brain Res. 1993 Jan 29;602(1):99–103. doi: 10.1016/0006-8993(93)90247-k. [DOI] [PubMed] [Google Scholar]
  13. Herrera D. G., Robertson H. A. Application of potassium chloride to the brain surface induces the c-fos proto-oncogene: reversal by MK-801. Brain Res. 1990 Feb 26;510(1):166–170. doi: 10.1016/0006-8993(90)90747-y. [DOI] [PubMed] [Google Scholar]
  14. Iwamoto T., Morita T., Kanazawa T., Ohtaka H., Ito K. Effects of KB-2796, a new calcium antagonist, and other diphenylpiperazines on [3H]nitrendipine binding. Jpn J Pharmacol. 1988 Oct;48(2):241–247. doi: 10.1254/jjp.48.241. [DOI] [PubMed] [Google Scholar]
  15. Iwamoto T., Morita T., Sukamoto T. Calcium antagonism by KB-2796, a new diphenylpiperazine analogue, in dog vascular smooth muscle. J Pharm Pharmacol. 1991 Aug;43(8):535–539. doi: 10.1111/j.2042-7158.1991.tb03532.x. [DOI] [PubMed] [Google Scholar]
  16. Jing J., Aitken P. G., Somjen G. G. Role of calcium channels in spreading depression in rat hippocampal slices. Brain Res. 1993 Feb 26;604(1-2):251–259. doi: 10.1016/0006-8993(93)90376-x. [DOI] [PubMed] [Google Scholar]
  17. Kanazawa T., Kidooka M., Matsuda M., Handa J. Effects of 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl) piperazine dihydrochloride, a new synthesized Ca2+ blocker KB-2796, on free fatty acid liberation in ischemic brain in rats. Nihon Geka Hokan. 1986 Nov 1;55(6):755–761. [PubMed] [Google Scholar]
  18. Kanazawa T., Morita T., Harada K., Iwamoto T., Ohtaka H., Sukamoto T., Ito K., Nurimoto S. Selective effect of KB-2796, a new calcium entry blocker, on cerebral circulation: a comparative study of the effects of calcium entry blockers on cerebral and peripheral arterial blood flows. J Cardiovasc Pharmacol. 1990 Sep;16(3):430–437. doi: 10.1097/00005344-199009000-00012. [DOI] [PubMed] [Google Scholar]
  19. Kanazawa T., Nakasu Y., Matsuda M., Handa J. [Acute effects of 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl) piperazine dihydrochloride, KB-2796, on cerebral blood flow in unanesthetized cats]. Nihon Geka Hokan. 1986 Sep 1;55(5):682–688. [PubMed] [Google Scholar]
  20. Kanazawa T., Toda N. [Inhibition by KB-2796, a new Ca2+ entry blocker, of the contractile response of isolated cerebral and peripheral arteries in the dog]. Nihon Yakurigaku Zasshi. 1987 Jun;89(6):365–373. doi: 10.1254/fpj.89.365. [DOI] [PubMed] [Google Scholar]
  21. Kruijer W., Cooper J. A., Hunter T., Verma I. M. Platelet-derived growth factor induces rapid but transient expression of the c-fos gene and protein. Nature. 1984 Dec 20;312(5996):711–716. doi: 10.1038/312711a0. [DOI] [PubMed] [Google Scholar]
  22. Lacombe P., Sercombe R., Correze J. L., Springhetti V., Seylaz J. Spreading depression induces prolonged reduction of cortical blood flow reactivity in the rat. Exp Neurol. 1992 Sep;117(3):278–286. doi: 10.1016/0014-4886(92)90137-f. [DOI] [PubMed] [Google Scholar]
  23. Lauritzen M., Hansen A. J., Kronborg D., Wieloch T. Cortical spreading depression is associated with arachidonic acid accumulation and preservation of energy charge. J Cereb Blood Flow Metab. 1990 Jan;10(1):115–122. doi: 10.1038/jcbfm.1990.14. [DOI] [PubMed] [Google Scholar]
  24. Lauritzen M., Jørgensen M. B., Diemer N. H., Gjedde A., Hansen A. J. Persistent oligemia of rat cerebral cortex in the wake of spreading depression. Ann Neurol. 1982 Nov;12(5):469–474. doi: 10.1002/ana.410120510. [DOI] [PubMed] [Google Scholar]
  25. Lauritzen M. Long-lasting reduction of cortical blood flow of the brain after spreading depression with preserved autoregulation and impaired CO2 response. J Cereb Blood Flow Metab. 1984 Dec;4(4):546–554. doi: 10.1038/jcbfm.1984.79. [DOI] [PubMed] [Google Scholar]
  26. Lauritzen M., Olesen J. Regional cerebral blood flow during migraine attacks by Xenon-133 inhalation and emission tomography. Brain. 1984 Jun;107(Pt 2):447–461. doi: 10.1093/brain/107.2.447. [DOI] [PubMed] [Google Scholar]
  27. Louis P. A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache. 1981 Nov;21(6):235–239. doi: 10.1111/j.1526-4610.1981.hed2106235.x. [DOI] [PubMed] [Google Scholar]
  28. Marrannes R., Willems R., De Prins E., Wauquier A. Evidence for a role of the N-methyl-D-aspartate (NMDA) receptor in cortical spreading depression in the rat. Brain Res. 1988 Aug 9;457(2):226–240. doi: 10.1016/0006-8993(88)90690-7. [DOI] [PubMed] [Google Scholar]
  29. Morgan J. I., Curran T. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci. 1991;14:421–451. doi: 10.1146/annurev.ne.14.030191.002225. [DOI] [PubMed] [Google Scholar]
  30. Moskowitz M. A., Nozaki K., Kraig R. P. Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci. 1993 Mar;13(3):1167–1177. doi: 10.1523/JNEUROSCI.13-03-01167.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Murphy T. H., Worley P. F., Baraban J. M. L-type voltage-sensitive calcium channels mediate synaptic activation of immediate early genes. Neuron. 1991 Oct;7(4):625–635. doi: 10.1016/0896-6273(91)90375-a. [DOI] [PubMed] [Google Scholar]
  32. Olesen J., Larsen B., Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981 Apr;9(4):344–352. doi: 10.1002/ana.410090406. [DOI] [PubMed] [Google Scholar]
  33. Ollat H. Agonistes et antagonistes de la sérotonine et migraine. Pathol Biol (Paris) 1992 Apr;40(4):389–396. [PubMed] [Google Scholar]
  34. Onodera H., Kogure K., Ono Y., Igarashi K., Kiyota Y., Nagaoka A. Proto-oncogene c-fos is transiently induced in the rat cerebral cortex after forebrain ischemia. Neurosci Lett. 1989 Mar 13;98(1):101–104. doi: 10.1016/0304-3940(89)90381-9. [DOI] [PubMed] [Google Scholar]
  35. Pavlásek J., Haburcák M., Masánová C., Orlický J. Increase of catecholamine content in the extracellular space of the rat's brain cortex during spreading depression wave as determined by voltammetry. Brain Res. 1993 Nov 19;628(1-2):145–148. doi: 10.1016/0006-8993(93)90949-n. [DOI] [PubMed] [Google Scholar]
  36. Saeki Y., Sato A., Sato Y., Trzebski A. Effects of stimulation of cervical sympathetic trunks with various frequencies on the local cortical cerebral blood flow measured by laser Doppler flowmetry in the rat. Jpn J Physiol. 1990;40(1):15–32. doi: 10.2170/jjphysiol.40.15. [DOI] [PubMed] [Google Scholar]
  37. Sambucetti L. C., Curran T. The Fos protein complex is associated with DNA in isolated nuclei and binds to DNA cellulose. Science. 1986 Dec 12;234(4782):1417–1419. doi: 10.1126/science.3491427. [DOI] [PubMed] [Google Scholar]
  38. Sheng M., Greenberg M. E. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron. 1990 Apr;4(4):477–485. doi: 10.1016/0896-6273(90)90106-p. [DOI] [PubMed] [Google Scholar]
  39. Siesjö B. K., Bengtsson F. Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis. J Cereb Blood Flow Metab. 1989 Apr;9(2):127–140. doi: 10.1038/jcbfm.1989.20. [DOI] [PubMed] [Google Scholar]
  40. Solomon G. D. Comparative efficacy of calcium antagonist drugs in the prophylaxis of migraine. Headache. 1985 Oct;25(7):368–371. doi: 10.1111/j.1526-4610.1985.hed2507368.x. [DOI] [PubMed] [Google Scholar]
  41. Solomon G. D., Steel J. G., Spaccavento L. J. Verapamil prophylaxis of migraine. A double-blind, placebo-controlled study. JAMA. 1983 Nov 11;250(18):2500–2502. [PubMed] [Google Scholar]
  42. Tamura T., Togawa T., Yokoyama K. Comparison of laser Doppler fluxmetry and the thermal diffusion method of measuring skin blood flow with hydrogen clearance. Int J Microcirc Clin Exp. 1992 Feb;11(1):95–107. [PubMed] [Google Scholar]
  43. Wauquier A., Ashton D., Marrannes R. The effects of flunarizine in experimental models related to the pathogenesis of migraine. Cephalalgia. 1985 May;5 (Suppl 2):119–123. doi: 10.1177/03331024850050S222. [DOI] [PubMed] [Google Scholar]
  44. Yoshidomi M., Hayashi T., Abe K., Kogure K. Effects of a new calcium channel blocker, KB-2796, on protein synthesis of the CA1 pyramidal cell and delayed neuronal death following transient forebrain ischemia. J Neurochem. 1989 Nov;53(5):1589–1594. doi: 10.1111/j.1471-4159.1989.tb08556.x. [DOI] [PubMed] [Google Scholar]

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