Abstract
A refined kainate (KA) C57BL/6J mouse model of status epilepticus (SE) using a repeated low dose (RLD) of KA (5 mg/kg, intraperitoneal; at 30 min intervals) was compared with the established single high dose (SHD) of KA (20 mg/kg, intraperitoneal) model. In the RLD group, increased duration of convulsive motor seizures (CMS, Racine scale stage ≥3) with a significant reduction in mortality from 21% to 6% and decreased variability in seizure severity between animals/batches were observed when compared to the SHD group. There was a significant increase in the percentage of animals that reached stage-5 seizures (65% versus 96%) in the RLD group. Integrated real-time video-EEG analysis of both groups, using NeuroScore software, revealed stage-specific spikes and power spectral density characteristics. When the seizures progressed from non-convulsive seizures (NCS, stage 1–2) to CMS (stage 3–5), the delta power decreased which was followed by an increase in gamma and beta power. A transient increase in alpha and sigma power marked the transition from NCS to CMS with characteristic ‘high frequency trigger’ spikes on the EEG, which had no behavioral expression. During SE the spike rate was higher in the RLD group than in the SHD group. Overall these results confirm that RLD of KA is a more robust and consistent mouse model of SE than the SHD of KA mouse model.
Highlights
Experimental animal models of seizures developed over many decades, have undergone numerous modifications in an effort to find the most appropriate preclinical model for screening antiepileptic drugs (AEDs), and secondarily to reduce and refine use of animals for in vivo experiments [1,2,3,4,5,6,7,8]
There was a significant increase in the percentage of animals that reached stage-5 seizures in the repeated low dose (RLD) group when compared to the single high dose (SHD) group (96% versus 65%; p = 0.001, unpaired t-test; Fig 2C–D)
The majority of RLD group animals remained at stage $3 more frequently once they reached stage-5 (Fig. 3B–D) while in the SHD group it varied from stage-1 to stage-5 (Fig. 3E)
Summary
Experimental animal models of seizures developed over many decades, have undergone numerous modifications in an effort to find the most appropriate preclinical model for screening antiepileptic drugs (AEDs), and secondarily to reduce and refine use of animals for in vivo experiments [1,2,3,4,5,6,7,8]. Rat models of seizure or epilepsy induced by chemoconvulsants such as the glutamate analogue, kainate (KA) and the cholinergic receptor agonist, pilocarpine have been commonly used for many years. Over the past two decades, chemoconvulsant mouse models of seizure and acquired epilepsy have begun to emerge with the intention of utilizing transgenic mice in epilepsy research. C57BL/6J mice are known to exhibit low sensitivity to chemoconvulsant induced seizures [21,22,23,24,25]
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