Flunarizine blocks voltage-gated Na(+) and Ca(2+) currents in cultured rat cortical neurons: A possible locus of action in the prevention of migraine.
Although flunarizine (FLN) has been widely used for migraine prophylaxis with clear success, the mechanisms of its actions in migraine prophylaxis are not completely understood. It has been hypothesized that migraine is a channelopathy, and abnormal activities of voltage-gated Na(+) and Ca(2+) channels might represent a potential mechanism of cortical hyperexcitability predisposing to migraine. The aim of the present study was to investigate the effects of FLN on Na(+) and Ca(2+) channels of cultured rat cortical neurons. Sodium currents (I(Na)) and calcium currents (I(Ca)) in cultured rat cortical neurons were monitored using whole-cell patch-clamp recordings. Both I(Na) and I(Ca) were blocked by FLN in a concentration-dependent manner with IC(50) values of 0.94μM and 1.77μM, respectively. The blockade of I(Na) was more powerful at more depolarizing holding potentials. The steady-state inactivation curve of I(Na) was shifted towards more hyperpolarizing potentials by FLN. FLN significantly delayed the recovery from fast inactivation of I(Na). Furthermore, the action of FLN in blocking I(Na) was enhanced at higher rates of channel activation. Blockades of these currents might help explain the mechanism underlying the preventive effect of FLN on migraine attacks.
Department of Neurology, the First Affiliated Hospital of Nanjing Medical University, Guangzhou Street 300, Nanjing, Jiangsu Province 210029, PR China.
Qing
Q
Ye
Lan-Yun
LY
Yan
Liu-Jun
LJ
Xue
Qiang
Q
Wang
Zhi-Kui
ZK
Zhou
Hiang
H
Xiao
Qi
Q
Wan
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D005444:Flunarizine / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008881:Migraine Disorders / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
D002121:Calcium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels; D005444:Flunarizine