title: Neuroprotection by lomerizine, a prophylactic drug for migraine, against hydrogen peroxide-induced hippocampal neurotoxicity.
abstract: Migraine is one of the risk factor for ischemic stroke. The purpose of this study was to examine the effect of lomerizine, a prophylactic drug for migraine, on H(2)O(2)-induced cell death of hippocampal neurons. Cytosolic Ca(2+) concentration was measured using fura-2 as a Ca(2+) indicator. Cell death was estimated by trypan blue exclusion. In rat-cultured hippocampal neurons, the addition of H(2)O(2) induced biphasic Ca(2+) elevations and cell death. The H(2)O(2)-induced biphasic Ca(2+) elevations and cell death only occurred when extracellular Ca(2+) was present. The biphasic Ca(2+) elevation was mediated by Ca(2+) influx through the plasma membrane, but not Ca(2+) release from the intracellular Ca(2+) store. Both the early and late phases of H(2)O(2)-induced Ca(2+) influx were reduced by either a T- or L-type voltage-dependent Ca(2+) channel (VDCC) blocker, lomerizine. In fact, L-type VDCC (α(1C) subunit) and T-type VDCC (α(1G) subunit) mRNA were expressed in rat hippocampal neurons. Although an L-type VDCC blocker, nifedipine, partly suppressed the late phase of Ca(2+) influx in response to H(2)O(2), a T-type VDCC blocker, mibefradil, reduced both phases of Ca(2+) influx. Moreover, lomerizine and mibefradil strongly reduced H(2)O(2)-induced cell death, and nifedipine weakly reduced it. These findings suggest that the inhibition of H(2)O(2)-induced Ca(2+) influx through T-type VDCC seems to be important in the protective effect of lomerizine against oxidative stress. It is possible that lomerizine may be a useful drug for prophylactic treatment of migraine, because migraine is a risk factor for ischemic stroke.
authors.affiliation: Department of Pathophysiology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. masakazu@pharm.showa-u.ac.jp
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ishii
authors.forename: Ryouta
authors.initials: R
authors.lastname: Iizuka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kiuchi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008881:Migraine Disorders / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000473:pathology; D009543:Nifedipine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D050052:TRPC Cation Channels / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism
chemical_list: D001549:Benzamides; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D010879:Piperazines; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels; C503500:Trpc5 protein, rat; C557080:Trpm2 protein, rat; D011189:Potassium Chloride; C025160:3-aminobenzamide; D006861:Hydrogen Peroxide; C052424:lomerizine; D009543:Nifedipine; D002118:Calcium