Abstracts

Introduction:Resistance to antiepileptic drugs is a major clinical problem affecting about 30 % of all epilepsy patients and up to 80 % of patients suffering from temporal lobe epilepsy. Surgical resection of ictogenic brain tissue is only feasible for a small minority of pharmacoresistant patients, therefore, developing novel pharmacological treatment strategies is an important goal of neurological research. The purinergic receptor system comprises of adenosine receptors and adenosine triphosphate (ATP)-activated P2-receptors. They are known to modulate synaptic transmission and are therefore regarded as potential pharmacological targets for new anticonvulsive drugs. The present in vitro study investigates adenosinergic modulation of induced epileptiform activity in human neocortical tissue.Methods:In total, 77 neocortical slices from 17 patients, who underwent epilepsy surgery between 2010 and 2015, were recorded. Local field potential recordings were obtained in layer V/VI of human neocortex. Stable epileptiform activity, so called seizure-like events (SLEs), were induced by elevating [K+] in artificial cerebrospinal fluid (aCSF) to 8 mM and adding 50 M of the GABAA receptor antagonist bicuculline-methiodide to the aCSF.Results:1 M of the selective A1 receptor agonist SDZ WAG 994 fully suppressed SLEs in 73 % of slices yielding a significantly higher proportion of slices where SLEs were blocked than 300 M of ATP (18 %) or 300 M of adenosine (13 %). The anticonvulsant effects of the high dose physiological broadband purinergic agonists ATP and adenosine were most likely mediated by A1 receptor activation. Moreover, SLEs which were resistant to 50 M carbamazepine (CBZ) were also blocked by the selective A1 agonist in 71 % of slices. No relevant effects on SLE parameters were observed by selectively antagonizing P2Y1, P2X1, P2X3, P2X2/3 and P2X7 receptors thus ruling out a possible endogenous P2 receptor mediated anticonvulsant effect. Conclusion:The main finding of the present study is a surprisingly high efficacy of the selective A1 agonist SDZ WAG 994 to block CBZ-resistant epileptiform events in human neocortex tissue. This study confirms the known anticonvulsant action of adenosine and, in addition, provides for the first time evidence for efficient, direct A1 receptor-mediated suppression of epileptiform activity in human neocortex tissue. Interestingly, SDZ WAG 994 has been shown to be tolerated by humans and thus may constitute a novel pharmacological approach to treating seizure disorders. Einleitung:Resistenz gegenber antiepileptischer Medikation ist ein bedeutendes klinisches Problem und betrifft circa 30 % aller Epilepsiepatienten und bis zu 80 % der Patienten mit Temporallappen-Epilepsie. Die chirurgische Resektion der iktogenen Hirnstrukturen ist nur fr eine kleine Minderheit der pharmakoresistenten Patienten mglich. Daher ist die Entwicklung von neuen pharmakologischen Behandlungen ein wichtiger Gegenstand der neurologischen Forschung. Das purinerge Rezeptorsystem besteht aus