A novel prophylactic effect of furosemide treatment on autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)

作者：Yannada, Junko; Zhu, Gang; Okada, Motohiro; Hirose, Shinichi; Yoshida, Shukuko; Shiba, Yuko; Migita, Keisuke; Mori, Fumiaki; Sugawara, Takayuki; Chen, Lei; Liu, Fang; Yoshida, Shuichi; Ueno, Shinya^*; Kaneko, Sunao

来源：Epilepsy Research, 2013, 107(1-2): 127-137.

DOI：10.1016/j.eplepsyres.2013.08.018

• ADNFLE
• CHRNA4
• GABA
• KCC2
• Furosemide
• Prophylactic medication

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 y-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-2C1 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 receptormediated 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 25 mg/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.

• 出版日期2013-11
• 单位中国医科大学