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First published on December 14, 2004; DOI: 10.1124/mol.104.007112

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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

Asher Peretz 1, Nurit Degani 1, Rachel Nachman 1, Yael Uziyel 1, Gilad Gibor 1, Doron Shabat 2, Bernard Attali 3*

1 Sacker Medical School, Tel Aviv University 2 School of Chemistry, Faculty of exact Sciences, Tel Aviv University 3 Sackler Medical School, Tel Aviv University

* Address correspondence to: E-mail: battali{at}post.tau.ac.il

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 {alpha} 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 {alpha}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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