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The need for improved antiepileptics is clearly mandated despite the existence of multiple existing medicines from different chemical and mechanistic classes. Standard of care agents do not fully control epilepsies and have a variety of side-effect and safety issues. Patients typically take multiple antiepileptic drugs and yet many continue to have seizures. Antiepileptic-unresponsive seizures are life-disrupting and life-threatening. One approach to seizure control is surgical resection of affected brain tissue and associated neural circuits. Although non-human brain studies can provide insight into novel antiepileptic mechanisms, human epileptic brain is the bottom-line biological substrate. Human epileptic brain can provide definitive information on the presence or absence of the putative protein targets of interest in the patient population, the potential changes in these proteins in the epileptic state, and the engagement of novel molecules and their functional impact in target tissue. In this review, we discuss data on two novel potential antiepileptic drugs. CERC-611 (LY3130481) is an AMPA receptor antagonist that selectively blocks AMPA receptors associated with the auxiliary protein TARP γ-8 and is in clinical development. KRM-II-81 is a positive allosteric modulator of GABA A receptors selectively associated with protein subunits α2 and α 3. Preclinical data on these compounds argue that patient-based biological data increase the probability that a newly discovered molecule will translate its antiepileptic potential to patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Some forms of epilepsy may arise as a result of pathologic interactions among neurons. Many forms of collective activity have been identified, including waves, spirals, oscillations, synchrony, and neuronal avalanches. All these emergent activity patterns have been hypothesized to show pathologic signatures associated with epilepsy. Here, the authors used 60-channel multielectrode arrays to record neuronal avalanches in cortical tissue removed from juvenile epilepsy patients. For comparison, they also recorded activity in rat cortical slices. The authors found that some human tissue removed from epilepsy patients exhibited prolonged periods of hyperactivity not seen in rat slices. In addition, they found a positive correlation between the branching parameter, a measure of network gain, and firing rate in human slices during periods of hyperactivity. This relationship was not present in rat slices. The authors suggest that this positive correlation between the branching parameter and the firing rate is part of a positive feedback loop and may contribute to some forms of epilepsy. These results also indicate that neuronal avalanches are abnormally regulated in slices removed from pediatric epilepsy patients.