title: Underlying mechanism of regulatory actions of diclofenac, a nonsteroidal anti-inflammatory agent, on neuronal potassium channels and firing: an experimental and theoretical study.
abstract: Diclofenac (DIC), a nonsteroidal anti-inflammatory drug, is known to exert anti-nociceptive and anti-convulsant actions; however, its effects on ion currents, in neurons remain debatable. We aimed to investigate (1) potential effects of diclofenac on membrane potential and potassium currents in differentiated NSC-34 neuronal cells and dorsal root ganglion (DRG) neurons with whole-cell patch-clamp technology, and (2) firing of action potentials (APs), using a simulation model from hippocampal CA1 pyramidal neurons based on diclofenac's effects on potassium currents. In the NSC-34 cells, diclofenac exerted an inhibitory effect on delayed-rectifier K⁺ current (I(KDR)) with an IC₅₀ value of 73 μM. Diclofenac not merely inhibited the I(KDR) amplitude in response to membrane depolarization, but also accelerated the process of current inactivation. The inhibition by diclofenac of IK(DR) was not reversed by subsequent application of either naloxone. Importantly, diclofenac (300 μM) increased the amplitude of M-type K⁺ current (I)(KM)), while flupirtine (10 μM) or meclofenamic acid (10 μM) enhanced it effectively. Consistently, diclofenac (100 μM) increased the amplitude of I(KM) and diminished the I(KDR) amplitude, with a shortening of inactivation time constant in DRG neurons. Furthermore, by using the simulation modeling, we demonstrated the potential electrophysiological mechanisms underlying changes in AP firing caused by diclofenac. During the exposure to diclofenac, the actions on both I(KM) and I(KDR) could be potential mechanism through which it influences the excitability of fast-spiking neurons. Caution needs to be made in attributing the effects of diclofenac primarily to those produced by the activation of I(KM).
authors: Department of Neurology, National Cheng Kung University Hospital, School of Medicine, National Cheng Kung University, Tainan City, Taiwan.
authors: C W
authors: CW
authors: Huang
authors: T Y
authors: TY
authors: Hung
authors: Y K
authors: YK
authors: Liao
authors: M C
authors: MC
authors: Hsu
authors: S N
authors: SN
authors: Wu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000927:Anticonvulsants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D004008:Diclofenac / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051656:KCNQ Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020033:Protein Isoforms / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D051670:Shaw Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D051656:KCNQ Potassium Channels; D049990:Membrane Transport Modulators; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D020033:Protein Isoforms; D051670:Shaw Potassium Channels; D004008:Diclofenac