Characterization of the intrahippocampal kainic acid model in female mice with a special focus on seizure suppression by antiseizure drugs and DMSO

Abstract

ABSTRACTObjectivesAffecting around 50 million people, men and women likewise, epilepsies are among the most common neurological diseases worldwide. Despite special challenges in the medical treatment of women with epilepsy, previous research has mainly focused on males, in particular preclinical animal studies, leaving a gap that needs to be urgently addressed. The intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy (TLE) as one of the most frequently studied models in males is used for screening of novel antiepileptic therapies. In this study we investigate the IHKA model of TLE in female mice, in particular drug-resistance of hippocampal paroxysmal discharges. Furthermore, we provide evidence for anti-seizure effects of dimethyl sulfoxide (DMSO) in epileptic, but not naÏve mice.MethodsAfter injecting KA unilaterally into the hippocampus of female mice, we monitored the development of epileptiform activity in in-vivo EEG recordings, evaluated responsiveness to the commonly prescribed antiseizure drugs (ASDs) lamotrigine (LTG), oxcarbazepine (OXC) and levetiracetam (LEV) and assessed typical neuropathological alterations of the hippocampus. Moreover, the effect of different doses of DMSO was tested in the IHKA chronic epilepsy model as well as on the PTZ-induced acute seizure threshold in both female and male mice.ResultsIn the IHKA model, female mice replicated the key features of human TLE (EEG and neuropathological changes). Importantly, hippocampal paroxysmal discharges (HPDs) in female mice did not respond to commonly prescribed ASDs, thus representing a suitable model of drug-resistant seizures. The solvent DMSO caused a significant short-term reduction of HPDs, but did not affect the threshold of acute seizures.SignificanceBy characterizing the drug-resistance of HPDs in the IHKA model of TLE in female mice we have laid a foundation for future research addressing sex-specific aspects. Considering the special issues complicating the therapeutic management of women, inclusion of females in the quest for novel treatment strategies is imperative. The observed effect of DMSO on epileptiform activity underlines that its application in epilepsy research is problematic and that the choice of solvent and appropriate vehicle control is crucial.