title: Benzodiazepines induce sequelae in immature mice with inflammation-induced status epilepticus.
abstract: OBJECTIVE
  Since benzodiazepines (BZPs) became clinically available for the treatment of status epilepticus (SE) in children, the incidence of neurological sequelae has increased. However, the cause-effect relationship is poorly understood. In this paper, we examined the effect of BZPs on an inflammation-induced SE (iSE) animal model.
  
  
  METHODS
  Inflammation was induced by injecting poly(I:C) (pIC 10 mg/kg, postnatal day 12-14), seizure was induced by injecting pilocarpine hydrochloride (PILO 200 mg/kg, postnatal day 15) into C57BL/6J mice, and the pIC+PILO mice were used as the iSE model (miSE). The GABA-A receptor agonist midazolam (MDL 0.5 mg/kg) was used to inhibit seizures. Sequelae were evaluated by performing behavior and immunohistochemical analyses in the chronic phase.
  
  
  RESULTS
  The exploratory activity of mice in the miSE plus MDL group increased significantly, indicating that hyperactivity was newly induced by MDL in miSE mice. The contextual fear memory of the miSE mice was also significantly increased and that of miSE treated with MDL returned to the normal level. The parvalbumin-positive GABA neurons were decreased in number by pIC+PILO which was rescued by MDL. Apoptosis marker ssDNA-positive cells were increased by pIC+PILO which could not be rescued by MDL. Therefore, we propose that BZP-dependent therapy for SE needs to be rethought from the perspective of using other treatment approaches.
authors.affiliation: Department of Brain Development and Neural Regeneration, Neural Development Project, Tokyo Metropolitan Institute of Medical Science, Japan; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Department of Brain Development and Neural Regeneration, Neural Development Project, Tokyo Metropolitan Institute of Medical Science, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Hirai
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Brain Development and Neural Regeneration, Neural Development Project, Tokyo Metropolitan Institute of Medical Science, Japan. Electronic address: okado-hr@igakuken.or.jp.
authors.forename: Haruo
authors.initials: H
authors.lastname: Okado
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000627:therapeutic use*; D003292:Convulsants; D005106:Exploratory Behavior / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000523:psychology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008874:Midazolam / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D010320:Parvalbumins; D010862:Pilocarpine; D011070:Poly I-C; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000523:psychology; D013226:Status Epilepticus / Q000188:drug therapy* / Q000209:etiology* / Q000523:psychology
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D018755:GABA Agonists; D010320:Parvalbumins; D011963:Receptors, GABA-A; D010862:Pilocarpine; D001569:Benzodiazepines; D011070:Poly I-C; D008874:Midazolam
keywords: Benzodiazepine; Children; GABA-A receptor; Inflammation; Status epilepticus