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Br J Pharmacol
2013 Mar 01;1685:1182-200. doi: 10.1111/bph.12065.
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The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential.
Boehlen A, Schwake M, Dost R, Kunert A, Fidzinski P, Heinemann U, Gebhardt C.
???displayArticle.abstract??? KCNQ2-5 channels are voltage-gated potassium channels that regulate neuronal excitability and represent suitable targets for the treatment of hyperexcitability disorders. The effect of Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was tested on KCNQ subtypes for its ability to alter neuronal excitability and for its anticonvulsant potential. The effect of 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was evaluated using whole-cell voltage-clamp recordings from CHO cells and Xenopus laevis oocytes expressing different types of KCNQ channels. Epileptiform afterdischarges were recorded in fully amygdala-kindled rats in vivo. Neuronal excitability was assessed using field potential and whole cell recording in rat hippocampus in vitro. 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a hyperpolarizing shift of the activation curve and a pronounced slowing of deactivation in KCNQ2-mediated currents, whereas KCNQ3/5 heteromers remained unaffected. The effect was also apparent in the Retigabine-insensitive mutant KCNQ2-W236L. In fully amygdala-kindled rats, it elevated the threshold for induction of afterdischarges and reduced seizure severity and duration. In hippocampal CA1 cells, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid strongly damped neuronal excitability caused by a membrane hyperpolarization and a decrease in membrane resistance and induced an increase of the somatic resonance frequency on the single cell level, whereas synaptic transmission was unaffected. On the network level, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a significant reduction of γ and θ oscillation peak power, with no significant change in oscillation frequency. Our data indicate that 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid is a potent KCNQ activator with a selectivity for KCNQ2 containing channels. It strongly reduces neuronal excitability and displays anticonvulsant activity in vivo.
Armand,
Effects of retigabine (D-23129) on different patterns of epileptiform activity induced by low magnesium in rat entorhinal cortex hippocampal slices.
2000, Pubmed
Armand,
Effects of retigabine (D-23129) on different patterns of epileptiform activity induced by low magnesium in rat entorhinal cortex hippocampal slices.
2000,
Pubmed Armand,
Effects of retigabine (D-23129) on different patterns of epileptiform activity induced by 4-aminopyridine in rat entorhinal cortex hippocampal slices.
1999,
Pubmed Biervert,
Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions.
1999,
Pubmed Biervert,
A potassium channel mutation in neonatal human epilepsy.
1998,
Pubmed
,
Xenbase Blackburn-Munro,
The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain.
2003,
Pubmed Blom,
Differential effects of ICA-27243 on cloned K(V)7 channels.
2010,
Pubmed
,
Xenbase Boehlen,
Effects of XE991, retigabine, losigamone and ZD7288 on kainate-induced theta-like and gamma network oscillations in the rat hippocampus in vitro.
2009,
Pubmed Boehlen,
Heterogeneous voltage dependence of interneuron resonance in the hippocampal stratum radiatum of adult rats.
2011,
Pubmed Boehlen,
The range of intrinsic frequencies represented by medial entorhinal cortex stellate cells extends with age.
2010,
Pubmed Brodie,
Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy.
2010,
Pubmed Brown,
Neural KCNQ (Kv7) channels.
2009,
Pubmed Brown,
Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone.
1980,
Pubmed Buzsáki,
Theta oscillations in the hippocampus.
2002,
Pubmed Charlier,
A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family.
1998,
Pubmed Chen,
Properties of single voltage-dependent K+ channels in dendrites of CA1 pyramidal neurones of rat hippocampus.
2004,
Pubmed Czuczwar,
Retigabine: the newer potential antiepileptic drug.
2010,
Pubmed Dalby-Brown,
K(v)7 channels: function, pharmacology and channel modulators.
2006,
Pubmed Delmas,
Pathways modulating neural KCNQ/M (Kv7) potassium channels.
2005,
Pubmed Du,
Characteristics and molecular basis of celecoxib modulation on K(v)7 potassium channels.
2011,
Pubmed Fanselow,
The amygdala, fear, and memory.
2003,
Pubmed Forcelli,
Anticonvulsant effect of retigabine during postnatal development in rats.
2012,
Pubmed Freeman,
The effect of interstimulation interval on the assessment and stability of kindled seizure thresholds.
1981,
Pubmed French,
Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy.
2011,
Pubmed Gao,
Isoform-specific prolongation of Kv7 (KCNQ) potassium channel opening mediated by new molecular determinants for drug-channel interactions.
2010,
Pubmed Gloveli,
Differential involvement of oriens/pyramidale interneurones in hippocampal network oscillations in vitro.
2005,
Pubmed Gu,
Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after-hyperpolarization and excitability control in CA1 hippocampal pyramidal cells.
2005,
Pubmed Hadley,
Stoichiometry of expressed KCNQ2/KCNQ3 potassium channels and subunit composition of native ganglionic M channels deduced from block by tetraethylammonium.
2003,
Pubmed Halliwell,
Voltage-clamp analysis of muscarinic excitation in hippocampal neurons.
1982,
Pubmed Hetka,
Retigabine strongly reduces repetitive firing in rat entorhinal cortex.
1999,
Pubmed Hu,
Complementary theta resonance filtering by two spatially segregated mechanisms in CA1 hippocampal pyramidal neurons.
2009,
Pubmed Hu,
Two forms of electrical resonance at theta frequencies, generated by M-current, h-current and persistent Na+ current in rat hippocampal pyramidal cells.
2002,
Pubmed Hu,
M-channels (Kv7/KCNQ channels) that regulate synaptic integration, excitability, and spike pattern of CA1 pyramidal cells are located in the perisomatic region.
2007,
Pubmed Hutcheon,
Resonance, oscillation and the intrinsic frequency preferences of neurons.
2000,
Pubmed Jensen,
The KCNQ5 potassium channel from mouse: a broadly expressed M-current like potassium channel modulated by zinc, pH, and volume changes.
2005,
Pubmed
,
Xenbase Jentsch,
Pathophysiology of KCNQ channels: neonatal epilepsy and progressive deafness.
2000,
Pubmed Jentsch,
Neuronal KCNQ potassium channels: physiology and role in disease.
2000,
Pubmed Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed Kristensen,
K(v) 7 (KCNQ) channel openers normalize central 2-deoxyglucose uptake in a mouse model of mania and increase prefrontal cortical and hippocampal serine-9 phosphorylation levels of GSK3β.
2012,
Pubmed Lamas,
Effects of a cognition-enhancer, linopirdine (DuP 996), on M-type potassium currents (IK(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons.
1997,
Pubmed Leão,
Kv7/KCNQ channels control action potential phasing of pyramidal neurons during hippocampal gamma oscillations in vitro.
2009,
Pubmed LeDoux,
Brain mechanisms of emotion and emotional learning.
1992,
Pubmed Lerche,
A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions.
1999,
Pubmed
,
Xenbase Linley,
M channel enhancers and physiological M channel block.
2012,
Pubmed Löscher,
Responses to NMDA receptor antagonists altered by epileptogenesis.
1991,
Pubmed Löscher,
Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations.
1988,
Pubmed Main,
Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine.
2000,
Pubmed
,
Xenbase Maljevic,
KV7 channelopathies.
2010,
Pubmed Marrion,
Control of M-current.
1997,
Pubmed McGrath,
Guidelines for reporting experiments involving animals: the ARRIVE guidelines.
2010,
Pubmed McNamara,
The kindling model of epilepsy: a review.
1980,
Pubmed Meldrum,
Identification and preclinical testing of novel antiepileptic compounds.
1997,
Pubmed Munro,
Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety.
2007,
Pubmed Otto,
Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission.
2002,
Pubmed Otto,
A spontaneous mutation involving Kcnq2 (Kv7.2) reduces M-current density and spike frequency adaptation in mouse CA1 neurons.
2006,
Pubmed
,
Xenbase Penschuck,
Changes in KCNQ2 immunoreactivity in the amygdala in two rat models of temporal lobe epilepsy.
2005,
Pubmed Peretz,
Pre- and postsynaptic activation of M-channels by a novel opener dampens neuronal firing and transmitter release.
2007,
Pubmed Peretz,
Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties.
2005,
Pubmed Peters,
Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior.
2005,
Pubmed
,
Xenbase Porter,
Retigabine.
2007,
Pubmed Puil,
Quantification of membrane properties of trigeminal root ganglion neurons in guinea pigs.
1986,
Pubmed Racine,
Modification of seizure activity by electrical stimulation. 3. Mechanisms.
1972,
Pubmed Rogawski,
New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels.
2008,
Pubmed Rostock,
D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures.
1996,
Pubmed Rundfeldt,
The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits.
2000,
Pubmed Rundfeldt,
The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells.
1997,
Pubmed Schenzer,
Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine.
2005,
Pubmed
,
Xenbase Schreiber,
Influence of ionic conductances on spike timing reliability of cortical neurons for suprathreshold rhythmic inputs.
2004,
Pubmed Schroeder,
KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents.
2000,
Pubmed Shah,
Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons.
2008,
Pubmed Tatulian,
Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine.
2001,
Pubmed Tober,
D-23129: a potent anticonvulsant in the amygdala kindling model of complex partial seizures.
1996,
Pubmed Tzingounis,
The KCNQ5 potassium channel mediates a component of the afterhyperpolarization current in mouse hippocampus.
2010,
Pubmed
,
Xenbase Wang,
KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel.
1998,
Pubmed
,
Xenbase Wickenden,
Kv7 channels as targets for the treatment of pain.
2009,
Pubmed Wickenden,
N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243): a novel, selective KCNQ2/Q3 potassium channel activator.
2008,
Pubmed Wuttke,
The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate.
2005,
Pubmed
,
Xenbase Xiong,
Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants.
2007,
Pubmed Xiong,
Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds.
2008,
Pubmed Yue,
KCNQ/M channels control spike afterdepolarization and burst generation in hippocampal neurons.
2004,
Pubmed
