Mefenamic acid bi-directionally modulates the transient outward K+ current in rat cerebellar granule cells.
The effect of non-steroidal anti-inflammatory drugs (NSAIDs) on ion channels has been widely studied in several cell models, but less is known about their modulatory mechanisms. In this report, the effect of mefenamic acid on voltage-activated transient outward K(+) current (I(A)) in cultured rat cerebellar granule cells was investigated. At a concentration of 5 microM to 100 microM, mefenamic acid reversibly inhibited I(A) in a dose-dependent manner. However, mefenamic acid at a concentration of 1 microM significantly increased the amplitude of I(A) to 113+/-1.5% of the control. At more than 10 microM, mefenamic acid inhibited the amplitude of I(A) without any effect on activation or inactivation. In addition, a higher concentration of mefenamic acid induced a significant acceleration of recovery from inactivation with an increase of the peak amplitude elicited by the second test pulse. Intracellular application of mefenamic acid could significantly increase the amplitude of I(A), but had no effect on the inhibition induced by extracellular mefenamic acid, implying that mefenamic acid may exert its effect from both inside and outside the ion channel. Furthermore, the activation of current induced by intracellular application of mefenamic acid was mimicked by other cyclooxygenase inhibitors and arachidonic acid. Our data demonstrate that mefenamic acid is able to bi-directionally modulate I(A) channels in neurons at different concentrations and by different methods of application, and two different mechanisms may be involved.
Zhang
Man
M
Institute of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200433, PR China.
Shi
Wen-Jie
WJ
Fei
Xiao-Wei
XW
Liu
Ya-Rong
YR
Zeng
Xi-Min
XM
Mei
Yan-Ai
YA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D016718:Arachidonic Acid / Q000633:toxicity; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000187:drug effects* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D051662:Kv1.1 Potassium Channel / Q000187:drug effects* / Q000502:physiology; D008528:Mefenamic Acid / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D051662:Kv1.1 Potassium Channel; D016718:Arachidonic Acid; D008528:Mefenamic Acid