A KCNQ channel opener for experimental neonatal seizures and status epilepticus.

Epileptic seizures occur commonly in the first days after birth.1 Such neonatal seizures are usually symptomatic, arising as a result of developmental abnormalities, in utero injuries, perinatal hypoxia-ischemia, infection, and other causes. Patients experiencing neonatal seizures are at substantial risk of mortality and long-term morbidity, including static encephalopathy, cerebral palsy, and chronic epilepsy.2, 3 The first-line drugs given to neonates, phenobarbital and phenytoin, are effective in less than 50% of cases4. Moreover, phenobarbital, benzodiazepines and phenytoin have been shown to cause widespread neuronal apoptosis when given to young rodents, raising concerns about administration of these drugs in human infants.5-7 The need for new treatments for neonatal seizures that are both safer and more effective has been widely acknowledged.1, 7, 8 Genetic, physiological, and pharmacological evidence calls attention to KCNQ potassium channels (also termed Kv7 and M-channels) as potential molecular targets for treatment of neonatal seizures.9 Loss-of-function mutations in the KCNQ2 and KCNQ3 genes cause benign familial neonatal seizures (BFNS), an uncommon but highly penetrant, dominantly-inherited syndrome characterized by seizures that recur frequently over the first weeks of life.10-12 Experimental inhibition of KCNQ channels in rodents, by pharmacological and genetic methods, dramatically promotes neuronal and network hyperexcitability and seizures in neonatal animals and in slices from neonatal brain; these effects diminish or disappear progressively with maturation. KCNQ2 and KCNQ3 are highly expressed on both myelinated and unmyelinated axons, and are strictly colocalized with clusters of voltage-gated sodium channels in the proximal axon (where action potentials initiate) and at the nodes of Ranvier.14, 17-19 It has been proposed that this strategic localization at the exact sites where action potentials arise and are conducted allows KCNQ channels to exert strong control over neuronal firing.17, 18 Selective neuronal KCNQ channel openers have been identified among drugs already in human use, including diclofenac (a widely used anti-inflammatory agent), flupirtine (a non-opioid analgesic in approved use in Europe) and retigabine (which is currently in phase 3 clinical trials for adult partial epilepsy in the U.S. and Europe).20-22 Additional potent and selective KCNQ channel openers have recently been discovered through directed high-throughput screening and have begun to be subjected to preclinical testing for adult epilepsy and pain.23-25 KCNQ openers increase channel activity significantly above normal levels by speeding opening rates, slowing closing rates, and reducing the membrane depolarization required for activation. Flupirtine and retigabine are close structural analogues (Figure 1). Flupirtine and retigabine have been shown to exhibit neuroprotective activity in several experimental systems, including models of infantile neuronal ceroid lipofuscinosis.26-28 Remarkably, KCNQ channel opener compounds have not been evaluated as a potential treatments for neonatal seizures or status epilepticus (SE). The human KCNQ2 and KCNQ3 channel loss-of-function phenotype, BFNS, suggests the channels are present, active and important during the neonatal period. Thus, augmenting KCNQ channel activity is a rational strategy for safe suppression of hyperexcitability during the neonatal period. Figure 1 Flupirtine and retigabine are close analogues In early trials using adult rodent models and adult human patients, flupirtine showed evidence of anti-epileptic efficacy.29 Here, we have tested flupirtine's utility for treatment of neonatal seizures and SE. We have compared flupirtine to two drugs widely used for neonatal seizures, phenobarbital and diazepam. In two well-established models, using the glutamate receptor agonist kainic acid or the convulsant gas flurothyl, flupirtine appeared more effective than either standard agent in preventing the onset of seizures in rat pups. In the kainic acid model, which produces seizures that evolve into SE lasting hours, flupirtine was more effective than either standard agent in diminishing the severity of electrographic and behavioral seizures. Indeed, flupirtine was effective even when its administration was withheld until after kainate-induced seizure activity had progressed to continuous SE. These findings indicate that KCNQ channel opener therapy for neonatal seizures deserves further investigation.