Received for publication September 13, 2004.
Revised November 22, 2004.
Accepted for publication December 9, 2004.

Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties

Abstract

The voltage-dependent M-type potassium current (M-current) plays a major role in controlling brain excitability by stabilizing the membrane potential and acting as a brake for neuronal firing. The KCNQ2/Q3 heteromeric channel complex was identified as the molecular correlate of the M-current. Furthermore, the KCNQ2 and KCNQ3 channel subunits are mutated in families with benign familial neonatal convulsions (BFNC), a neonatal form of epilepsy. Enhancement of KCNQ2/Q3 potassium currents may provide an important target for anti-epileptic drug development. Here we show that meclofenamic acid (meclofen) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers. Extracellular application of meclofen (EC₅₀ = 25 µM) and diclofenac (EC₅₀ = 2.6 µM) resulted in the activation of KCNQ2/Q3 K⁺ currents, heterologously expressed in Chinese hamster ovary (CHO) cells. Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (-23 mV and -15 mV, respectively) and by markedly slowing the deactivation kinetics. The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel subunits. In contrast, they did not enhance KCNQ1 K⁺ currents. Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential. In cultured cortical neurons, meclofen and diclofenac enhanced the M-current, reduced evoked and spontaneous action potentials, while in vivo diclofenac exhibited an anti-convulsant activity (ED₅₀ = 43 mg/kg). These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine or neuropathic pain.

Key words: Ion channel regulation, Potassium, Regulation - physiological, Structure/function/mechanism

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