title: A novel prophylactic effect of furosemide treatment on autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).
abstract: The transgenic rat strain S284L-TG harbors the S284L mutant of the neuronal nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4), which is responsible for human autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). S284L-TG rats have epileptic seizure phenotypes during slow-wave sleep, similar to those in NFLE. We previously demonstrated that γ-aminobutyric acid (GABA)ergic action of these rats was suppressed before the onset of ADNFLE seizures, and that glutamate release in the epileptic focus lesion was increased at the onset of epilepsy. Here, mRNA analysis revealed that Cl(-)-accumulating Na-K-2Cl cotransporter 1 (NKCC1) levels were increased and Cl(-)-extruding K-Cl cotransporter 1 and 2 (KCC1 and KCC2) levels were decreased at the onset of ADNFLE seizures in S284L-TG rat frontal cortexes, which perturbed the GABAergic inhibitory system. The reversal potentials (EGABA) of GABAA receptor-mediated currents in cortical layer V pyramidal neurons of S284L-TG rats also changed their polarity from hyperpolarization to depolarization, and S284L-TG miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs), significantly increased in both amplitude and frequency. Administration of 25mg/kg/day furosemide before, but not after, the onset of interictal discharges prevented idiopathic epileptic activity, reversed the depolarizing shift of EGABA and increased mEPSC amplitude to normal levels. These data indicate that early treatment with an agent that normalizes pathogenesis has a prophylactic effect on epilepsy. We propose a strategy for prophylactic medication against idiopathic epilepsy through the suppression of epileptogenesis and/or ictogenesis.
authors.affiliation: Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: jyamada@cc.hirosaki-u.ac.jp.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamada
authors.forename: Gang
authors.initials: G
authors.lastname: Zhu
authors.forename: Motohiro
authors.initials: M
authors.lastname: Okada
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirose
authors.forename: Shukuko
authors.initials: S
authors.lastname: Yoshida
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shiba
authors.forename: Keisuke
authors.initials: K
authors.lastname: Migita
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Mori
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sugawara
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yoshida
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueno
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D004569:Electroencephalography; D017034:Epilepsy, Frontal Lobe / Q000188:drug therapy* / Q000235:genetics; D005665:Furosemide / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D055647:Rats, Transgenic; D011978:Receptors, Nicotinic / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D005665:Furosemide; D011978:Receptors, Nicotinic
keywords: ADNFLE; CHRNA4; Furosemide; GABA; KCC2; Prophylactic medication