Abstract

Neuroinflammation in chronic diseases, such as epilepsy, may be the cause of the tissue dysfunction that characterizes the disease. The hemichannels formed by connexin43 (Cx43 HCs) expressed by glial cells contribute to neuroinflammation characterized by an increase in cytoplasmic Ca2+. This favors the synthesis and release of pro-inflammatory molecules that promote the release of glutamate and ATP, causing seizures. Current antiepileptic drugs (AEDs), such as valproate, have a pleiotropic action on neuronal molecular targets and their action on glial HCs remains elusive. Through molecular docking studies, we predicted the preferred binding orientation of valproate on Cx43 HCs, suggesting that it could directly affect the activity of HCs. Our experimental results indicate that valproate increases the activity of Cx43 HCs in an exogenous expression system. The effect of valproate was more evident in cells preincubated in the absence of extracellular divalent cations when the HC open probability is increased. This is consistent with the bioinformatic study, since the predicted binding site of valproate to Cx43 HC is on the intracellular side, so valproate could be entering through the HCs when they activity is increased due to reduction of the extracellular Ca2+, which occurs during seizures. Valproate also increases the ATP release through Cx43 HCs, suggesting that it promotes neuroinflammation, which may contribute to explaining why ~30% of epileptic patients are drug-refractory.