# An Evaluation of Cation–Chloride Cotransporters NKCC1 and KCC2 in Carbamazepine-Resistant Rats

## TL;DR

This study explores how cation-chloride cotransporters and adenosine receptors affect drug-resistant epilepsy in rats.

## Contribution

The study reveals a new therapeutic role of adenosine receptors in modulating NKCC1 levels in drug-resistant epilepsy.

## Key findings

- The combination of bumetanide and probenecid shows anticonvulsant effects in carbamazepine-resistant rats.
- Adenosine receptor activation modulates NKCC1 protein levels in the hippocampus of resistant animals.
- NKCC1 and KCC2 protein expression changes are observed in carbamazepine-resistant rats.

## Abstract

Approximately one-third of epileptic patients do not respond adequately to drug therapy, leading to the development of drug-resistant epilepsy. Given the established role of dysregulated expression of two cation–chloride cotransporter proteins, NKCC1 and KCC2, in susceptibility to convulsion generation and epilepsy development, the present study evaluates the anticonvulsant potential of bumetanide (BUM, 10 mg/kg, i.p.) and probenecid (PROB, 50 mg/kg, i.p.), the potential of adenosine receptor activation (NECA, 1 mg/kg, i.p.) to modify the anticonvulsant efficacy of BUM, and the changes in NKCC1 and KCC2 protein expression levels in carbamazepine (CBZ)-resistant animals. In the window–pentylenetetrazole (PTZ) kindling model, male Wistar rats that undergo full kindling develop CBZ-resistance. The combination of BUM + PROB appears to have an anticonvulsant effect on CBZ-resistant convulsions, while alterations in the protein levels of the NKCC1 and KCC2 cotransporters are observed in CBZ-resistant animals. Despite the absence of therapeutic efficacy in managing convulsions through adenosine receptor activation (BUM + NECA), the activation of adenosine receptors exhibits the capacity to modulate the levels of the NKCC1 protein in the hippocampus of CBZ-resistant animals. This effect provides the initial evidence for a new therapeutic role of adenosine receptors in regulating the pathological levels of NKCC1 in drug-resistant epilepsy.