Pathology-selective antiepileptic effects in the focal freeze-lesion rat model of malformation of cortical development

Exp Neurol. 2021 May 28:113776. doi: 10.1016/j.expneurol.2021.113776. Online ahead of print.ABSTRACTMalformations of cortical development (MCD) represent a group of rare diseases with severe clinical presentation as epileptic and pharmacoresistant encephalopathies. Morphological studies in tissue from MCD patients have revealed reduced GABAergic efficacy and increased intracellular chloride concentration in neuronal cells as important pathophysiological mechanisms in MCD. Also, in various animal models, alterations of GABAergic inhibition have been postulated as a predominant factor contributing to perilesional hyperexcitability. Along with this line, the NKCC1 inhibitor bumetanide has been postulated as a potential drug for treatment of epilepsy, mediating its antiepileptic effect by reduction of the intracellular chloride and increased inhibitory efficacy of GABAergic transmission. In the present study, we focused on the focal freeze-lesion model of MCD to compare antiepileptic drugs with distinct mechanisms of action, including NKCC1 inhibition by bumetanide. For this purpose, we combined electrophysiological and optical methods in slice preparations and assessed the properties of seizure like events (SLE) induced by 4-aminopyridine. In freeze-lesioned but not control slices, SLE onset was confined to the perilesional area, confirming that this region is hyperexcitable and likely triggers pathological activity. Bumetanide selectively reduced epileptic activity in lesion-co...
Source: Experimental Neurology - Category: Neurology Authors: Source Type: research