title: Age- and region-specific effects of anticonvulsants and bumetanide on 4-aminopyridine-induced seizure-like events in immature rat hippocampal-entorhinal cortex slices.
abstract: OBJECTIVE
  Seizure-like events (SLEs) induced by 4-aminopyridine in rat organotypic slices cultures, which are prepared early after birth, are resistant to standard antiepileptic drugs. In this study we tested the hypothesis that pharmacoresistance may be an intrinsic property of the immature brain.
  
  
  METHODS
  Frequently recurring SLEs presumably representing status epilepticus were induced by 4-aminopyridine in acute rat hippocampal-entorhinal cortex slices obtained from postnatal day 3-19 (P3-P19), and the effects of carbamazepine, phenytoin, valproic acid, and phenobarbital were examined. In addition, bumetanide was tested, which blocks the Na(+) -K(+) -2Cl(-) (NKCC1) cotransporter, and also acetazolamide, which blocks the carbonic anhydrase and thereby the accumulation of bicarbonate inside neurons.
  
  
  RESULTS
  The efficacy of all antiepileptic drugs in blocking SLEs was dependent on postnatal age, with low efficacy in P3-P5 slices. Antiepileptic drugs suppressed SLEs more readily in the medial entorhinal cortex (ECm) than in the CA3. In P3-P5 slices, valproic acid and phenobarbital increased both tonic and clonic seizure-like activities in the CA3, whereas phenytoin and carbamazepine blocked tonic-like but prolonged clonic-like activity. In P3-P5 slices, bumetanide often blocked SLEs in the CA3, but was not as effective in the ECm. Like with other antiepileptic drugs, the seizure-suppressing effects of acetazolamide increased with postnatal age.
  
  
  CONCLUSIONS
  We conclude that pharmacoresistance may be inherent to very immature tissue and suggest that expression of the NKCC1 cotransporter might contribute to pharmacoresistance.
authors.affiliation: Institute of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Abdul
authors.initials: A
authors.lastname: Wahab
authors.forename: Klaus
authors.initials: K
authors.lastname: Albus
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinemann
mesh_terms: D015761:4-Aminopyridine / Q000633:toxicity*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D002034:Bumetanide / Q000494:pharmacology* / Q000627:therapeutic use; D018728:Entorhinal Cortex / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D002034:Bumetanide; D015761:4-Aminopyridine