The Anti-Epileptic Effects of Carbenoxolone In Vitro and In Vivo.

Anna Volnova,Janaina M Alves,Vassiliy Tsytsarev,Grace E Vélez-Crespo,Olga Ganina,Alla Ignashchenkova,Mikhail Inyushin

doi:10.3390/ijms23020663

Abstract

Gap junctions (GJs) are intercellular junctions that allow the direct transfer of ions and small molecules between neighboring cells, and GJs between astrocytes play an important role in the development of various pathologies of the brain, including regulation of the pathological neuronal synchronization underlying epileptic seizures. Recently, we found that a pathological change is observed in astrocytes during the ictal and interictal phases of 4-aminopyridin (4-AP)-elicited epileptic activity in vitro, which was correlated with neuronal synchronization and extracellular epileptic electrical activity. This finding raises the question: Does this signal depend on GJs between astrocytes? In this study we investigated the effect of the GJ blocker, carbenoxolone (CBX), on epileptic activity in vitro and in vivo. Based on the results obtained, we came to the conclusion that the astrocytic syncytium formed by GJ-associated astrocytes, which is responsible for the regulation of potassium, affects the formation of epileptic activity in astrocytes in vitro and epileptic seizure onset. This effect is probably an important, but not the only, mechanism by which CBX suppresses epileptic activity. It is likely that the mechanisms of selective inhibition of GJs between astrocytes will show important translational benefits in anti-epileptic therapies.

Highlights

Accepted: 6 January 2022Epilepsy is a widespread disease of the central nervous system resulting from abnormal neural synchronization, which causes recurring seizures spreading across the brain.Its main feature is the sudden onset of synchronized activity of many neurons, leading to various pathological psychomotor manifestations [1]
We described periodic signals in the astrocyte syncytium during the interictal phase of 4-AP-elicited epileptic seizures, and these signals were correlated with synchronized neuronal spikes, while ictal events were correlated with profound depolarization of the astrocyte syncytium and with vasomotion [14]
After perfusion of the slice preparation for 30–60 s with 2 mM 4-AP dissolved in artificial cerebrospinal fluid (ACSF), the inward current oscillations started to appear in astrocytes, with a mean amplitude of 37.7 ± 2.3 pA

Summary

Introduction

Epilepsy is a widespread disease of the central nervous system resulting from abnormal neural synchronization, which causes recurring seizures spreading across the brain. Its main feature is the sudden onset of synchronized activity of many neurons, leading to various pathological psychomotor manifestations [1]. Pharmacological agents, diet, deep brain stimulation, and, in severe cases, neurosurgical treatment are used for antiepileptic therapy. Despite great progress in the development of new anti-epileptic drugs, a significant number of cases of epilepsy are pharmacoresistant. Many antiepileptic drugs have significant side effects. There is an urgent need for further study of epileptogenesis and the development of new antiepileptic drugs

Methods

Results

Discussion

Conclusion