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 or pannexin1 (Cx43 HCs and Panx1 HCs, respectively) expressed by glial (Cx43 HCs) and neuronal (Panx1 HCs) cells contribute to neuroinflammation characterized by increase in cytoplasmic Ca2+. This favors the synthesis and release of pro-inflammatory molecules that promote release of glutamate and ATP, causing seizures. Current antiepileptic drugs (AEDs) have a pleiotropic action on neuronal molecular targets and their action on glial HCs remains elusive. Our results indicate that carbamazepine and valproate, two widely used AEDs, increase the activity of Cx43 and Panx1 HCs in an exogenous expression system, suggesting that they promote neuroinflammation, which may contribute to explain why ~30% of epileptic patients are drug-refractory. Through molecular docking studies, we suggest that these AEDs could directly increase the activity of HCs. Furthermore, D4, a selective Cx HC blocker, prevented the increase in cell membrane permeability by pentylenetetrazol, an epileptogenic drug that block GABAA channels in cells of ex-vivo hippocampal slices, and in hippocampal cells of pentylentetrazol-treated animals. Then, new molecules with antiepileptic and HCs blockade activity were searched using a structure-based virtual screening strategy. Several molecules with good binding affinities to Cx43 and Panx1 HC, and to other receptors and channels involved in epilepsy were found. Studies are underway to prove their selectivity and potency. Inhibitors of antiepileptic compounds that also block Cx43 and/or Panx1 HC could be useful to improve the epilepsy treatment.