Benzodiazepines induce sequelae in immature mice with inflammation-induced status epilepticus

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. Method: 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. Result: 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. (C) 2015 Elsevier Inc. All rights reserved.