title: Tenidap, an agonist of the inwardly rectifying K+ channel Kir2.3, delays the onset of cortical epileptiform activity in a model of chronic temporal lobe epilepsy.
abstract: OBJECTIVE
  Inwardly rectifying K(+) (Kir) channel, Kir2.3, has been found down-regulated in the hippocampus of chronic temporal lobe epileptic (cTLE) patients which may underline the mechanism of epilepsy. Tenidap is an agonist of Kir2.3. However, the effect of tenidap on cTLE remains obscure. The aim of the present study was to observe the relationship between Kir2.3 and the pathogenesis of cTLE, and to explore the potential effect of Kir agonists as anti-epileptic drugs.
  
  
  METHODS
  The pilocarpine temporal lobe epilepsy (TLE) rat model was established and status epilepticus (SE) was induced in rats. The rats were divided into four groups based on time points (0 hours, 6 hours, 72 hours, and two weeks) after SE termination. The dynamic changes in Kir2.3 mRNA and protein expression in the hippocampus were detected at each time point by reverse transcription polymerase chain reaction (RT-PCR) and western blotting to determine an appropriate time for further intervention and observation. Then, tenidap was administered and its effect on the expression of Kir2.3 mRNA/protein and the electroencephalogram (EEG) wave was documented at predetermined time points.
  
  
  RESULTS
  The pattern of Kir2.3 mRNA and protein expression was bimodal, as it increased immediately after SE and declined at two weeks, when compared with the control group. Down-regulation of the Kir channels may lead to an impaired clearance of K(+) ions from the extracellular space and result in a stronger neuronal depolarisation. Two weeks after SE may be a reversal point. Spontaneous recurrent seizures (SRS) appeared at the two-week point, indicating that chronic epilepsy had occurred. Tenidap up-regulated expressions of both Kir2.3 channel mRNA and protein, which may help to maintain the resting membrane potential (RMP) and hyperpolarisation of the cells.
  
  
  CONCLUSIONS
  Our results suggest that the down-regulation of the Kir2.3 channel expression might contribute to the pathogenesis of TLE, which may be ameliorated by the administration of tenidap.
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Hao
authors.forename: Xunyi
authors.initials: X
authors.lastname: Wu
authors.forename: Peimin
authors.initials: P
authors.lastname: Yu
authors.forename: Guoxing
authors.initials: G
authors.lastname: Zhu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hong
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000517:prevention & control*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D000078183:Oxindoles; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists* / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D007211:Indoles; C490968:Kcnj4 protein, rat; D000078183:Oxindoles; D024661:Potassium Channels, Inwardly Rectifying; C062866:tenidap