Epilepsia
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Cognitive comorbidities are increasingly recognized as an equal (or even more disabling) aspect of epilepsy. In addition, the actions of some antiseizure drugs (ASDs) can impact learning and memory. Accordingly, the National Institute of Neurological Disorders and Stroke (NINDS) epilepsy research benchmarks call for the implementation of standardized protocols for screening ASDs for their amelioration or exacerbation of cognitive comorbidities. Long-term potentiation (LTP) is a widely used model for investigating synaptic plasticity and its relationship to learning and memory. Although the effects of some ASDs on LTP have been examined, none of these studies employed physiologically relevant induction stimuli such as theta-burst stimulation (TBS). To systematically evaluate the effects of multiple ASDs in the same preparation using physiologically relevant stimulation protocols, we examined the effects of a broad panel of existing ASDs on TBS-induced LTP in area CA1 of in vitro brain slices, prepared in either normal or sucrose-based artificial cerebrospinal fluid (ACSF), from C57BL/6 mice. ⋯ The results of experiments describe herein provide a comprehensive summary of the effects of many commonly used ASDs on short- and long-term synaptic plasticity while, for the first time, using physiologically relevant LTP induction protocols and slice preparations from mice. Furthermore, methodologic variables, such as brain slice preparation protocols, were explored. These results provide comparative knowledge of ASD effects on synaptic plasticity in the mouse hippocampus and may ultimately contribute to an understanding of the differences in the cognitive side effect profiles of ASDs and the prediction of cognitive dysfunction associated with novel investigational ASDs.
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Altered thalamic GABAA-receptor subunit expression in the stargazer mouse model of absence epilepsy.
Absence seizures, also known as petit mal seizures, arise from disruptions within the cortico-thalamocortical network. Interconnected circuits within the thalamus consisting of inhibitory neurons of the reticular thalamic nucleus (RTN) and excitatory relay neurons of the ventral posterior (VP) complex, generate normal intrathalamic oscillatory activity. The degree of synchrony in this network determines whether normal (spindle) or pathologic (spike wave) oscillations occur; however, the cellular and molecular mechanisms underlying absence seizures are complex and multifactorial and currently are not fully understood. Recent experimental evidence from rodent models suggests that regional alterations in γ-aminobutyric acid (GABA)ergic inhibition may underlie hypersynchronous oscillations featured in absence seizures. The aim of the current study was to investigate whether region-specific differences in GABAA receptor (GABAAR) subunit expression occur in the VP and RTN thalamic regions in the stargazer mouse model of absence epilepsy where the primary deficit is in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression. ⋯ These findings suggest that region-specific differences in GABAAR subunits in the thalamus of epileptic mice, specifically up-regulation of GABAARs in the thalamic relay neurons of the VP, may contribute to generation of hypersynchronous thalamocortical activity in absence seizures. Understanding region-specific differences in GABAAR subunit expression could help elucidate some of the cellular and molecular mechanisms underlying absence seizures and thereby identify targets by which drugs can modulate the frequency and severity of epileptic seizures. Ultimately, this information could be crucial for the development of more specific and effective therapeutic drugs for treatment of this form of epilepsy.
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Randomized Controlled Trial Multicenter Study
Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial.
To evaluate the safety and tolerability of adjunctive brivaracetam (BRV), a high-affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures. ⋯ Adjunctive BRV given at individualized tailored doses (20-150 mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures.
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Randomized Controlled Trial Multicenter Study
Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial.
Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand currently being investigated for the treatment of epilepsy. The purpose of this phase III study was to evaluate the efficacy and safety/tolerability of adjunctive BRV in adults with uncontrolled partial-onset (focal) seizures. ⋯ Adjunctive BRV at a daily dose of 50 mg was associated with statistically significant reductions in seizure frequency compared with PBO. All doses of BRV showed good tolerability throughout the study.
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Randomized Controlled Trial Multicenter Study
Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial.
Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand in clinical development for the treatment of epilepsy. This phase III study (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients aged 16-70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage. ⋯ In this study of adjunctive BRV (20-100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline-adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. BRV 20-100 mg/day was well tolerated without up-titration, with a high completion rate.