Currently, more than 30% of epilepsy patients are not responsive to commercially available antiepileptic drugs (AEDs), highlighting a substantial need to develop new drugs for treating the debilitating condition. Preclinical screening for safety and efficacy is an important step in developing these AEDs, and finding the most appropriate animal model to mirror drug-resistant epilepsy in humans is vital.
Over the last two decades, mice that are genetically predisposed to exhibit low sensitivity to AEDs (C57BL/6J strain) have emerged as a promising model for screening. However, previous studies suggest that exposing the strain to the glutamate receptor agonist kainate (KA), a seizure-inducing drug commonly used in preclinical studies, results in an unpredictable seizure response, even when doses are consistent. This is a research disadvantage because when seizures don’t reliably meet severity and duration thresholds, investigators are unable to get a clear picture of the experimental state. Another disadvantage is that previous studies have demonstrated high mortality rates associated with administering KA to the strain. Lower mortality rates result in more useable data and help with reduction and refinement of experimental animals.
Before dismissing C57BL/6J as an impractical model, researchers conducted a study1 to determine whether the dosing method for administering KA—repeated low doses (RLD) versus a single high dose (SHD)—would affect seizure quality and mortality in C57BL/6J mice. Using behavioral and electroencephalography (EEG) indicators, the study showed that RLD of KA did result in a higher percentage of animals achieving prolonged convulsive motor seizures, less inter-animal variability of seizure stages, a higher spike rate per minute, and less mortality. Interestingly, this study also provided evidence of a new sub-stage on the behavioral seizure scale.
Ultimately, by demonstrating the advantages of the RLD method, the study showed that the C57BL/6J strain can be a robust, consistent model for studying the effects of AEDs on drug-resistant subjects. The study also provided important information on seizure stages and EEG spike characteristics that could open the door to further refining the animal models used for such research.
DSI solutions played an important role in the study, helping the researchers acquire and analyze EEG and activity data. PhysioTel™ ETA-F20 implants were used in 18 of the mice studied to wirelessly detect EEG, movement activity, and body temperature information. In addition to providing valuable information for all seizure stages, the EEG data were essential for identifying the short “high frequency trigger” spike period that is not associated with behavioral indications. Additionally, the real-time video and EEG recording captured using Dataquest A.R.T.™ acquisition software helped the researchers score the observed behavioral stages. EEG recordings and activity data were analyzed using NeuroScore™ software.
Tse, K., Puttachary, S., Beamer, E., Sills, G. J. & Thippeswamy, T. (2014). Advantages of Repeated Low Dose Against Single High Dose of Kainate in C57BL/6J Mouse Model of Status Epilepticus: Behavioral and Electroencephalographic Studies. PLoS ONE 9(5): e96622. Doi: 10.1371/journal.pone.0096622
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