8Th European Congress on Epileptology, Berlin, Germany, 21 – 25 September 2008
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Epilepsia, 50(Suppl. 4): 2–262, 2009 doi: 10.1111/j.1528-1167.2009.02063.x 8th ECE PROCEEDINGS 8th European Congress on Epileptology, Berlin, Germany, 21 – 25 September 2008 Sunday 21 September 2008 KV7 channels (KV7.1-5) are encoded by five genes (KCNQ1-5). They have been identified in the last 10–15 years by discovering the caus- 14:30 – 16:00 ative genes for three autosomal dominant diseases: cardiac arrhythmia Hall 1 (long QT syndrome, KCNQ1), congenital deafness (KCNQ1 and KCNQ4), benign familial neonatal seizures (BFNS, KCNQ2 and VALEANT PHARMACEUTICALS SATELLITE SYM- KCNQ3), and peripheral nerve hyperexcitability (PNH, KCNQ2). The fifth member of this gene family (KCNQ5) is not affected in a disease so POSIUM – NEURON-SPECIFIC M-CURRENT K+ CHAN- far. The phenotypic spectrum associated with KCNQ2 mutations is prob- NELS: A NEW TARGET IN MANAGING EPILEPSY ably broader than initially thought (i.e. not only BFNS), as patients with E. Perucca severe epilepsies and developmental delay, or with Rolando epilepsy University of Pavia, Italy have been described. With regard to the underlying molecular pathophys- iology, it has been shown that mutations in KCNQ2 and KCNQ3 Innovations in protein biology, coupled with genetic manipulations, have decrease the resulting K+ current thereby explaining the occurrence of defined the structure and function of many of the voltage- and ligand- epileptic seizures by membrane depolarization and increased neuronal gated ion channels, channel subunits, and receptors that are the underpin- firing. Very subtle changes restricted to subthreshold voltages are suffi- nings of neuronal hyperexcitability and epilepsy. Of the currently cient to cause BFNS which proves in a human disease model that this is available antiepileptic drugs (AEDs), no two act in the same way, but all the relevant voltage range for these channels to modulate the firing rate. target components of Na+ channels, Ca2+ channels, the GABA system, The two mutations associated with PNH induce much more severe glutamate receptors, or modulatory sites involved in transmitter release, channel dysfunction with a dominant negative effect on wild type (WT) alone or in combination. None targets primarily the endogenous braking channels. action of M-type potassium current on repetitive firing and neuronal KV7 channels represent interesting targets for new therapeutic excitability. Although M-current was first identified in 1980 as a slowly approaches to diseases caused by neuronal hyperexcitability, such as epi- activating, noninactivating voltage-gated subthreshold potassium cur- lepsy, neuropathic pain, and migraine. The molecular mechanism of rent, its molecular correlates – a family of KCNQ (Kv7) channels – were KV7 activation by retigabine has been recently elucidated as a stabiliza- only identified in 1996 and are now recognized as novel molecular targets tion of the open conformation by binding to the pore region. for new AEDs. This symposium will address the need for AEDs with novel mechanisms, review recent discoveries related to the structure and function of neuron-specific potassium/M-current channels, and summa- rize the evidence that these channels are therapeutic targets in epilepsy PHARMACOLOGY OF M-CURRENT K+ CHANNEL based on preclinical and clinical studies with the potassium channel ACTIVATION opener retigabine. H. S. White University of Utah, Salt Lake City, UT, USA Much of what is known about the therapeutic potential of M-current acti- THE NEED FOR NOVEL ANTIEPILEPTIC DRUGS vators is based on observations with retigabine (N-[2-amino-4-(-4-fluor- J. French obenzylamino)-phenyl]carbamic acid ethyl ester) since it is the only New York University Comprehensive Epilepsy Center, New York, agent among the established and investigational antiepileptic drugs (AEDs) that enhances the M-current at therapeutic doses. By enhancing NY, USA M-currents, retigabine decreases neuronal excitability by inhibiting spike-frequency adaptation. At concentrations (>10 lmol) higher than No Abstract Received. mean peak concentrations (2–6 lmol) achieved with therapeutic dosages of retigabine, retigabine may enhanceGABAA receptor-mediated chlo- ride currents through a nonbenzodiazepine action. Seizure models in which retigabine has shown activity include electrical (MES), chemical ANATOMY AND PHYSIOLOGY OF M-CURRENT K+ (PTZ, picrotoxin, penicillin, kainate, i.c.v. administered NMDA), and genetic (genetically epilepsy prone rats and audiogenic seizure suscepti- CHANNELS ble mice) seizures. Retigabine has been found to be effective in blocking H. Lerche the fully expressed behavioral seizure and decreasing the electrographic University of Ulm, Ulm, Germany afterdischarge duration in the fully kindled rat model of partial epilepsy. It is also highly effective in two models of pharmacoresistant epilepsy, Voltage-gated K+ channels of the KV7 (KCNQ) family underlie the i.e., the mouse 6 Hz psychomotor seizure test and the amygdala-kindled so-called M current, a K+ current that is suppressed by activation of rat rendered resistant to lamotrigine and other sodium channel blockers. muscarinic acetylcholine receptors. This current is found in many Retigabine also prevents the acquisition of kindling in the amygdala kin- neurons of the central nervous system and regulates their firing behavior. dled rat and enhances learning performance in a model of cerebral ische- A major subcellular localization of these channels is the axon initial seg- mia. The broad-spectrum activity of retigabine in animal seizure models ment, the site of action potential generation at which also voltage-gated demonstrates that the M-current plays an important role in the control of Na+ channels are concentrated. The functional role of M channels there membrane excitability and control of seizure activity. Moreover, the pre- is to serve as a brake for action potential firing. Therefore, pharmacologi- clinical profile of retigabine establishes the M-current as a legitimate cal activation of these channels represents a potent anticonvulsant mech- molecular target for epilepsy management and for further development anism that is not in clinical use up to now. of M-current activators. 2 3 8th ECE Proceedings CLINICAL EVIDENCE FOR POTASSIUM/M-CURRENT the brain, induced for example by an initial precipitating injury occurring CHANNELS AS A THERAPEUTIC TARGET IN EPI- at birth or during the lifetime, initiates a cascade of events in the CNS that contributes to setting the basis for the late onset of epilepsy. Chronic LEPSY inflammatory reactions in the brain can enhance neuronal excitability, J. French endanger neuronal survival, and alter blood–brain barrier permeability New York University Comprehensive Epilepsy Center, New York, [1–3]; each of these effects may contribute to epileptogenesis [4]. Experi- NY, USA mental observations also show that seizures per se can trigger inflamma- tion in the brain involving both the innate and the adaptive immune As the only antiepileptic drug (AED) to directly activate (open) KCNQ systems and sharing molecules and pathways also activated by systemic (Kv7) channels, which are the molecular correlates of M-current, retiga- infection [5,6]. If a relation between inflammation and epilepsy were to bine provides the first opportunity to evaluate the potential of this new be proven, it might open new opportunities for the treatment of seizures therapeutic class in epilepsy management. Its pharmacokinetic profile is and possibly the retardation of epileptogenesis or progression of the characterized by a half-life of 8–10 hours, metabolism by hydrolysis/ disease. N-acetylation and glucuronidation (nonoxidative pathways), primarily renal elimination, and low potential for pharmacokinetic drug inter- References actions. The efficacy and tolerability/safety of retigabine as adjunctive 1. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental therapy in adults with partial-onset seizures has been established in dou- and clinical evidence. Epilepsia 2005;46(11):1724–43. ble-blind, placebo-controlled trials, showing a clear-cut dose-response 2. Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. relationship. During 16 to 18 weeks of double-blind treatment, seizures Nat Rev Immunol 2005;5(8):629–40. were reduced >50% in 29%–40% of patients receiving retigabine 600– 3. Vezzani A, Baram TZ. New roles for interleukin-1 beta in the mecha- 1200 mg/day vs. 17% of those assigned to placebo. Seizures were nisms of epilepsy. Epilepsy Curr 2007;7(2):45–50. reduced >50% in 35%–50% of patients receiving retigabine 600–1200 4. Pitknen A, Sutula TP. Is epilepsy a progressive disorder? Prospects mg/day vs. 22% of those assigned to placebo during the maintenance for new therapeutic approaches in temporal-lobe epilepsy. Lancet phase. Discontinuations due to adverse events were 9% in patients receiv- Neurol 2002;1(3):173–81. ing placebo and 15%–28% in retigabine-treated patients, depending on 5. De Simoni MG, Perego C, Ravizza T et al. Inflammatory cytokines retigabine dose, occurring most frequently during a titration period that and related genes are induced in the rat hippocampus by limbic status allowed very little or no flexibility to improve tolerability or retention as epilepticus. Eur J Neurosci 2000;12(7):2623–33. the starting dosage of 300 mg/day (100 mg t.i.d.) retigabine was 6. Turrin NP, Rivest S. Innate immune reaction in response to seizures: increased weekly in 150 mg/day increments to the assigned target dosage. implications for the