Anti-epileptogenesis: Electrophysiology, diffusion tensor imaging and behavior in a genetic absence model

Abstract

The beneficial effects of chronic and early pharmacological treatment with ethosuximide on epileptogenesis were studied in a genetic absence epilepsy model comorbid for depression. It was also investigated whether there is a critical treatment period and treatment length. Cortical excitability in the form of electrical evoked potentials, but also to cortico-thalamo-cortical network activity (spike–wave discharges, SWD and afterdischarges), white matter changes representing extra corticothalamic functions and depressive-like behavior were investigated. WAG/Rij rats received either ethosuximide for 2 months (post natal months 2–3 or 4–5), or ethosuximide for 4 months (2–5) in their drinking water, while control rats drank plain water. EEG measurements were made during treatment, and 6 days and 2 months post treatment. Behavioral test were also done 6 days post treatment. DTI was performed ex vivo post treatment. SWD were suppressed during treatment, and 6 days and 2 months post treatment in the 4 month treated group, as well as the duration of AD elicited by cortical electrical stimulation 6 days post treatment. Increased fractional anisotropy in corpus callosum and internal capsula on DTI was found, an increased P8 evoked potential amplitude and a decreased immobility in the forced swim test. Shorter treatments with ETX had no large effects on any parameter. Chronic ETX has widespread effects not only within but also outside the circuitry in which SWD are initiated and generated, including preventing epileptogenesis and reducing depressive-like symptoms. The treatment of patients before symptom onset might prevent many of the adverse consequences of chronic epilepsy.

WONOEP appraisal: Network concept from an imaging perspective

“…The network understanding gained through fMRI has also guided potential therapeutic interventions for restoring consciousness during focal seizures through electrical or optogenetic stimulation of subcortical arousal systems . BOLD fMRI with electrophysiologic verification and diffusion‐tensor imaging (DTI) have also yielded crucial insights into mechanisms of seizure generation as well as developmental epileptogenesis and epilepsy prevention …”

“…42,43 BOLD fMRI with electrophysiologic verification and diffusion-tensor imaging (DTI) have also yielded crucial insights into mechanisms of seizure generation 38,44,45 as well as developmental epileptogenesis and epilepsy prevention. [46][47][48][49] | 1297 WYKES Et al.…”

The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis

“…On the other hand, the antiepileptogenic effects of chronic ETX was accompanied by a decrease in depressive-like behaviour in WAG/Rij rats (Sarkisova et al, 2010;van Luijtelaar et al, 2013). Considering that epileptogenesis and chronic ETX treatment inducing antiepileptogenesis might affect mood and cognitive processes such as learning and memory, these latter processes were additionally investigated in a cue discrimination learning task in an Y-maze (problem solving task) and in a sucrose motivation task during and after chronic treatment.…”

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

“…The number, but not duration, of the SWDs was found to be markedly suppressed during 3 months of sequential recordings performed after termination of treatment, revealing an antiepileptogenic potential of ethosuximide. This observation has been reproduced in subsequent studies [17,31] and extended to another genetic animal model for human absence epilepsy-the GAERS rat [32]. Furthermore, ethosuximide also seems to prevent comorbid anxiety [32] and depression [31,33] in the genetic absence epilepsy models, based upon observations in the open field and the forced swim test, respectively.…”

“…Treatment duration seems of importance, as one study in WAG/Rij rats showed that treatment for 4 months was required, whereas a shorter treatment duration of 2 months was ineffective [31]. All studies with ethosuximide have so far been conducted with treatment initiated prior to onset of SWD, and have not examined whether chronic treatment initiated after the onset of SWD would also provide antiepileptogenic effects.…”