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: Masakazu Ishii, Ryouta Iizuka, Yuji Kiuchi, Yasuo Mori, Shunichi Shimizu
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 358 Issue 1-2 Pg. 1-11 (Dec 2011) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 21656126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Calcium Channel Blockers
• Neuroprotective Agents
• Piperazines
• TRPC Cation Channels
• TRPM Cation Channels
• Trpc5 protein, rat
• Trpm2 protein, rat
• Potassium Chloride
• 3-aminobenzamide
• Hydrogen Peroxide
• lomerizine
• Nifedipine
• Calcium

Topics

• Animals
• Benzamides (pharmacology)
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology)
• Cell Death (drug effects)
• Cells, Cultured
• HEK293 Cells
• Hippocampus (drug effects, pathology)
• Humans
• Hydrogen Peroxide (toxicity)
• Intracellular Space (drug effects, metabolism)
• Ion Channel Gating (drug effects)
• Migraine Disorders (drug therapy, pathology, prevention & control)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Neurotoxicity Syndromes (drug therapy, pathology)
• Nifedipine (pharmacology)
• Piperazines (pharmacology, therapeutic use)
• Potassium Chloride (pharmacology)
• Rats
• Rats, Wistar
• TRPC Cation Channels (metabolism)
• TRPM Cation Channels (metabolism)