Regulation of Potassium and Chloride Concentrations in Nervous Tissue as a Method of Anticonvulsant Therapy

Abstract

Abstract Under some pathological conditions, such as pharmacoresistant epilepsy, status epilepticus or certain forms of genetic abnormalities, spiking activity of GABAergic interneurons may enhance excitation processes in neuronal circuits and provoke the generation of ictal discharges. As a result, anticonvulsants acting on the GABAergic system may be ineffective or even increase seizure activity. This paradoxical effect of the inhibitory system is due to ionic imbalances in nervous tissue. This review addresses the mechanisms of ictal discharge initiation in neuronal networks due to the imbalance of chloride and potassium ions, as well as possible ways to regulate ionic concentrations. Both the enhancement (or attenuation) of the activity of certain neuronal ion transporters and ion pumps and their additional expression via gene therapy can be effective in suppressing seizure activity caused by ionic imbalances. The Na+–K+-pump, NKCC1 and KCC2 cotransporters are important for maintaining proper K+ and Cl– concentrations in nervous tissue, having been repeatedly considered as pharmacological targets for antiepileptic exposures. Further progress in this direction is hampered by the lack of sufficiently selective pharmacological tools and methods for providing effective drug delivery to the epileptic focus. The use of the gene therapy techniques, such as overexpressing of the KCC2 transporter in the epileptic focus, seems to be a more promising approach. Another possible direction could be the use of optogenetic tools, namely specially designed light-activated ion pumps or ion channels. In this case, photon energy can be used to create the required gradients of chloride and potassium ions, although these methods also have significant limitations which complicate their rapid introduction into medicine.