TEMPORAL lobe epilepsy could be better controlled by enhancing the activity of a key neuronal transporter, according to new research showing that boosting potassium–chloride cotransporter 2 (KCC2) reduced abnormal brain activity and prevented seizures in experimental models of the disease.
Temporal lobe epilepsy is one of the most common forms of focal epilepsy and is frequently resistant to medication. Mesial temporal lobe epilepsy, in particular, often fails to respond to conventional antiseizure therapies, leaving many patients with persistent seizures and limited treatment options. Researchers therefore investigated whether restoring chloride balance in neurons, a process regulated by KCC2, could help suppress the abnormal electrical signalling that drives seizures.
Role of KCC2 in Neuronal Inhibition
KCC2 plays a central role in maintaining the chloride gradient across neuronal membranes. This gradient determines how effectively γ-aminobutyric acid (GABA), the brain’s main inhibitory neurotransmitter, can dampen neuronal firing. When KCC2 expression or function is reduced, inhibitory GABA signalling may become less effective, potentially contributing to the hyperexcitability seen in temporal lobe epilepsy.
Compounds Enhance KCC2 Function in Cortical Neurons
To explore whether restoring KCC2 activity could counteract this dysfunction, researchers examined two small molecules identified as potential enhancers of the transporter: prochlorperazine, a commonly prescribed anti-emetic, and CLP-257. Laboratory experiments in cortical neurons showed that both compounds increased KCC2 function by promoting its clustering on the neuronal cell membrane and reducing its diffusion within the membrane. Notably, this effect occurred without altering established phosphorylation pathways that typically regulate KCC2.
Further electrophysiological analysis revealed that CLP-257 selectively increased extrasynaptic GABA-A receptor–mediated currents, suggesting that enhanced KCC2 activity could strengthen inhibitory signalling in neuronal networks.
Targeting Temporal Lobe Epilepsy Activity in Human Tissue
The investigators then assessed whether these molecular effects translated into seizure suppression. Recordings from resected brain tissue obtained from patients with drug-resistant mesial temporal lobe epilepsy showed that both compounds markedly reduced spontaneous epileptiform activity.
Similar results were observed in a mouse model of temporal lobe epilepsy. Administration of prochlorperazine or CLP-257 (or its prodrug CLP-290), significantly decreased seizure frequency in vivo, providing further evidence that enhancing KCC2 function could stabilise neuronal networks.
Although the findings represent an important proof of concept, the researchers noted that the work was largely preclinical and additional studies will be needed to evaluate safety, dosing, and long-term effects in humans. Nevertheless, the results suggest that targeting chloride homeostasis through KCC2 enhancement may offer a promising therapeutic strategy for patients with drug-resistant temporal lobe epilepsy.
A Growing Trend of Anti-Emetics as Anti-Epileptics
These findings are part of a broader trend, as other anti-emetic drugs have also demonstrated anti-epileptic effects. For example, studies in animal models have shown that ondansetron and tropisetron, medications commonly used for nausea, can reduce seizure frequency, improve cognitive function, and protect neurons in temporal lobe epilepsy. Such evidence highlights the potential for repurposing well-established anti-nausea medications as novel therapies for drug-resistant epilepsy.
Reference
Donneger F et al. Enhancing KCC2 function reduces interictal activity and prevents seizures in temporal lobe epilepsy. Proc Natl Acad Sci USA. 2026; DOI:10.1073/pnas.2522722123.
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