Dimethylethanolamine Decreases Epileptiform Activity in Acute Human Hippocampal Slices in vitro

Abstract

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy with about 30% of patients developing pharmacoresistance. These patients continue to suffer from seizures despite polytherapy with antiepileptic drugs (AEDs) and have an increased risk for premature death, thus requiring further efforts for the development of new antiepileptic therapies. The molecule dimethylethanolamine (DMEA) has been tested as a potential treatment in various neurological diseases, albeit the functional mechanism of action was never fully understood. In this study, we investigated the effects of DMEA on neuronal activity in single-cell recordings of primary neuronal cultures. DMEA decreased the frequency of spontaneous synaptic events in a concentration-dependent manner with no apparent effect on resting membrane potential (RMP) or action potential (AP) threshold. We further tested whether DMEA can exert antiepileptic effects in human brain tissue ex vivo. We analyzed the effect of DMEA on epileptiform activity in the CA1 region of the resected hippocampus of TLE patients in vitro by recording extracellular field potentials in the pyramidal cell layer. Epileptiform burst activity in resected hippocampal tissue from TLE patients remained stable over several hours and was pharmacologically suppressed by lacosamide, demonstrating the applicability of our platform to test antiepileptic efficacy. Similar to lacosamide, DMEA also suppressed epileptiform activity in the majority of samples, albeit with variable interindividual effects. In conclusion, DMEA might present a new approach for treatment in pharmacoresistant TLE and further studies will be required to identify its exact mechanism of action and the involved molecular targets.

An Eluate of the Medicinal Plant Garcinia kola Displays Strong Antidiabetic and Neuroprotective Properties in Streptozotocin-Induced Diabetic Mice

“…Beyond their well-established antimicrobial properties, β -lactam compounds may participate in the extensively reported anti-inflammatory and antidiabetic activities of G. kola seeds [ 21 – 23 ] and some β -lactam compounds were reported to show antiparkinsonian and hypoglycemic activities [ 54 – 56 ]. Notably, dimethylethanolamine (DMEA), a close molecular relative to N , N -dimethylethanolamine, is an established cholinergic antidepressive agent with therapeutic properties against dementia, dyskinesia, and epilepsy [ 57 , 58 ]. Interestingly, the neuroactivity profiles of N , N -dimethylethanolamine and N -ethyl-2-carboxyazetidine are unknown.…”

Spatiotemporal Correlation of Epileptiform Activity and Gene Expression in vitro

“…In human slices, c-FOS expression correlated with epileptiform activity, but we did not find increased expression in the onset zone, most likely due a high variability of the SLE onset and consequently probable imprecise definition. This onset variability as compared to rat tissue is likely due to the overall variability of human tissue obtained from different patients with consequent impact on the activity in vitro ( Andersson et al, 2016 ; Wickham et al, 2018 ; Kraus et al, 2019 ) and also due to differences in tissue or different slicing angles ( Kraus et al, 2020 ). All these variables not only influence neuronal survival and network excitability, but also could have affected gene expression.…”

“…In human brain slices, the application of neither 4-AP alone nor 10 or 12 mM potassium is sufficient to induce epileptiform activity ( Gabriel et al, 2004 ). Therefore, SLEs were evoked by applying a combination of high potassium (8 mM) and 4-AP (100 μM), while adjusting the increased osmolarity of aCSF by lowering the concentration of NaCl from 129 to 124 mM ( Kraus et al, 2019 ).…”

In vitro human cell culture models in a bench‐to‐bedside approach to epilepsy

“…fibroblasts/blood cells, iPSCs derived 2D neural cell cultures, 22 iPSCs derived 3D neural cell cultures, 22 direct reprogrammed neural cell cultures, 23,24 resected human brain tissue cultures. 25 T A B L E 3 Comparison of general and epilepsy related parameters studied using in vitro patient derived cell culture models, including appropriate methodologies (non neural cell cultures e.g. fibroblasts/blood cells, [29][30][31][32][33][34] iPSCs derived 2D neural cell cultures, [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] iPSCs derived 3D neural cell cultures, 32,50,51,52,53,54,55,56,57,58,59,60,61 direct reprogrammed neural cell cultures, 44,62,63,64 resected human brain tissue cultures).…”

“…fibroblasts/blood cells, [29][30][31][32][33][34] iPSCs derived 2D neural cell cultures, [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] iPSCs derived 3D neural cell cultures, 32,50,51,52,53,54,55,56,57,58,59,60,61 direct reprogrammed neural cell cultures, 44,62,63,64 resected human brain tissue cultures). 25,26,65,66,67,68,69,70,71,72 other cell model systems. Second, nonneural somatic cells provide insight into the cellular pathophysiological processes of the individual case without the need to access the brain tissue from surgical resection.…”