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

Abstract

Under some pathological conditions, such as pharmacoresistantepilepsy, status epilepticus or certain forms of genetic abnormalities,spiking activity of GABAergic interneurons may enhance excitationprocesses in neuronal circuits and provoke the generation of ictaldischarges. As a result, anticonvulsants acting on the GABAergicsystem may be ineffective or even increase seizure activity. Thisparadoxical effect of the inhibitory system is due to ionic imbalancesin nervous tissue. This review addresses the mechanisms of ictaldischarge initiation in neuronal networks due to the imbalance ofchloride and potassium ions, as well as possible ways to regulateionic concentrations. Both the enhancement (or attenuation) of theactivity of certain neuronal ion transporters and ion pumps andtheir additional expression via gene therapy can be effective insuppressing seizure activity caused by ionic imbalances. The Na+–K+-pump,NKCC1 and KCC2 cotransporters are important for maintaining properK+ and Cl– concentrationsin nervous tissue, having been repeatedly considered as pharmacologicaltargets for antiepileptic exposures. Further progress in this directionis hampered by the lack of sufficiently selective pharmacologicaltools and methods for providing effective drug delivery to the epilepticfocus. The use of the gene therapy techniques, such as overexpressingof the KCC2 transporter in the epileptic focus, seems to be a more promisingapproach. Another possible direction could be the use of optogenetictools, namely specially designed light-activated ion pumps or ionchannels. In this case, photon energy can be used to create therequired gradients of chloride and potassium ions, although thesemethods also have significant limitations which complicate theirrapid introduction into medicine.