title: 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 alpha subunits are mutated in families with benign familial neonatal convulsions, a neonatal form of epilepsy. Enhancement of KCNQ2/Q3 potassium currents may provide an important target for antiepileptic drug development. Here, we show that meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers. Extracellular application of meclofenamate (EC(50) = 25 microM) and diclofenac (EC(50) = 2.6 microM) resulted in the activation of KCNQ2/Q3 K(+) currents, heterologously expressed in Chinese hamster ovary cells. Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (-23 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, meclofenamate and diclofenac enhanced the M-current and reduced evoked and spontaneous action potentials, whereas in vivo diclofenac exhibited an anticonvulsant activity (ED(50) = 43 mg/kg). These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine, or neuropathic pain.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Asher
authors.initials: A
authors.lastname: Peretz
authors.forename: Nurit
authors.initials: N
authors.lastname: Degani
authors.forename: Rachel
authors.initials: R
authors.lastname: Nachman
authors.forename: Yael
authors.initials: Y
authors.lastname: Uziyel
authors.forename: Gilad
authors.initials: G
authors.lastname: Gibor
authors.forename: Doron
authors.initials: D
authors.lastname: Shabat
authors.forename: Bernard
authors.initials: B
authors.lastname: Attali
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D006224:Cricetinae; D004008:Diclofenac / Q000494:pharmacology*; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D008469:Meclofenamic Acid / Q000494:pharmacology*; D010655:Phenylenediamines / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C496915:Kcnq2 protein, rat; C496918:Kcnq3 protein, rat; D010655:Phenylenediamines; D024642:Potassium Channels, Voltage-Gated; C101866:ezogabine; D004008:Diclofenac; D008469:Meclofenamic Acid