Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy

Abstract

Summary Purpose Ethosuximide (ESX) is a drug of choice for the symptomatic treatment of absence seizures. Chronic treatment with ESX has been reported to have disease-modifying anti-epileptogenic activity in the WAG/Rij rat model of genetic generalised epilepsy (GGE) with absence seizures. Here we examined whether chronic treatment with ESX (i) possesses anti-epileptogenic effects in the GAERS model of GGE, (ii) is associated with a mitigation of behavioural comorbidities, and (iii) influences gene expression in the somatosensory cortex region where seizures are thought to originate. Methods GAERS and Non-Epileptic Control (NEC) rats were chronically treated with ESX (in drinking water) or control (tap water) from 3 to 22 weeks of age. Subsequently, all animals received tap water only for another 12 weeks to assess enduring effects of treatment. Seizure frequency and anxiety-like behaviours were serially assessed throughout the experimental paradigm. Treatment effects on the expression of key components of the epigenetic molecular machinery, the DNA methyltransferase enzymes, were assessed using qPCR. Key findings ESX treatment significantly reduced seizures in GAERS during the treatment phase, and this effect was maintained during the 12 weeks post-treatment phase (p<0.05). Further, the anxiety-like behaviours present in GAERS were reduced by ESX treatment (p<0.05). Molecular analysis revealed that ESX treatment was associated with increased expression of DNA methyltransferase enzyme mRNA in cortex. Significance Chronic ESX treatment has disease-modifying effects in the GAERS model of GGE, with anti-epileptogenic effects against absence seizures and mitigation of behavioural comorbidities. The cellular mechanism for these effects may involve epigenetic modifications.

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

“…In the WAG/Rij rat model of absence epilepsy, early prophylactic treatment with ethosuximide, levetiracetam, or zonisamide (but not carbamazepine) before the onset of spike-wave discharges in the EEG suppressed the development of such absence-like seizures [31][32][33], which was also subsequently observed in the GAERS model of absence epilepsy [34]. These findings suggest that models are available in which epileptogenesis can be controlled and that early treatment during development may provide a strategy for preventing genetic epilepsy in susceptible individuals.…”

Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial

“…It is difficult to know at this time whether the striking reduction in the risk of developing GTCs in those assigned to ethosuximide (even many years later when off the medication) represents a disease modification effect, as was suggested by an observational study 12 and by animal data. 13,14 Longer duration of follow-up with focus on remission outcomes is in progress and may provide a more definitive answer. However, the data provide compelling evidence that concern about the occurrence of GTCs should not change the status of ethosuximide as the preferred first-line therapy for CAE.…”

Monogenic models of absence epilepsy

“…The corollary applies to seizure termination, which may depend on reversal of tonic inhibition through still undefined endogenous mechanisms. A second issue of clinical importance is the recent finding that early treatment with ethosuximide hinders the epileptogenesis of absence epilepsy in both humans (Berg et al, 2014) and rodents (Dezsi et al, 2013). Since drug treatment does not correct the genetic mutation, it must drive altered activity-dependent changes in developmental gene expression that raise the threshold for oscillations, including those that regulate the strength of feedforward inhibition.…”