Summary: For the brain to stay calm, it relies on a “braking system” called GABAergic signaling. In patients with temporal lobe epilepsy, this system fails because of a chloride imbalance: neurons become overloaded with chloride, turning GABA from a “brake” into an “accelerator” that triggers seizures.
A new study has identified two molecules—prochlorperazine (PCPZ) and CLP-257—that can fix this. By stabilizing a crucial ion transporter called KCC2, these molecules restore the brain’s natural inhibitory balance. Most notably, the treatment almost completely suppressed electrical discharges in human brain tissue and reduced seizure frequency by up to 55% in animal models.
Key Facts
- The KCC2 Failure: KCC2 is responsible for pumping chloride out of neurons. In epilepsy, this pump fails, causing GABA signaling to paradoxically excite neurons rather than inhibit them.
- Spatial Stabilization: The identified molecules don’t just increase the amount of KCC2; they cause the transporter to cluster into dense, efficient patches on the neuron’s surface.
- Human Validation: Researchers tested the molecules on living brain tissue from 13 patients with treatment-resistant epilepsy, observing a nearly complete suppression of spontaneous electrical spikes.
- Seizure Reduction: In chronic epilepsy models, prochlorperazine reduced seizure frequency by 40%, while CLP-290 (a derivative of CLP-257) reduced it by 55%.
- Repurposing Potential: Prochlorperazine is an FDA-approved antipsychotic and anti-nausea drug, meaning its safety profile is already known, potentially accelerating its path to becoming a new epilepsy treatment.
Source: Paris Brain Institute
For the brain to function normally, it must continuously regulate its electrical activity. One of the key mechanisms involved is GABAergic signaling, a natural inhibitory system that controls neuronal activity and prevents the electrical bursts that characterize epileptic seizures. This braking system depends on a delicate balance: the concentration of chloride inside neurons.
An ion transporter known as KCC2 is responsible for removing excess chloride from nerve cells. When it functions poorly—as observed in many neurological disorders, including mesial temporal lobe epilepsy, the most common form of focal epilepsy in adults—chloride accumulates inside neurons. As a result, GABAergic signals, instead of inhibiting neuronal activity, can paradoxically excite it.
“Continuously pumping chloride out of neurons is very costly in ATP, the cell’s fuel. When neurons are under stress, they tend to neglect this mechanism, probably to preserve their metabolism and energy reserves.
“As a result, KCC2 activity is greatly reduced in epilepsy. My team set out to find a way to stimulate it,” explains Jean-Christophe Poncer, co-leader of the EpiC team at the Paris Brain Institute.
Two Molecules to Strengthen a Failing Transporter
Using high-throughput screening, two compounds—prochlorperazine (PCPZ) and CLP-257—had previously been identified for their ability to restore chloride balance in neurons. Prochlorperazine is an antipsychotic drug approved in the 1950s to treat nausea, migraines, and certain psychiatric disorders.
CLP-257, meanwhile, had already been studied in the context of neuropathic pain. However, the potential antiepileptic effects of these two molecules had never been explored.
Jean-Christophe Poncer’s team first studied rat hippocampal neurons and showed that both compounds significantly improved KCC2 efficiency by restoring the chloride gradient, thereby allowing GABAergic signaling to regain its inhibitory function.
But how do these molecules work?
“Contrary to what one might expect, PCPZ and CLP-257 do not increase the amount of KCC2 in nerve cells. Instead, they act more subtly by changing the way the transporter aggregates at the surface of neurons and by promoting its clustering into dense patches,” says Jean-Christophe Poncer. “This spatial stabilization makes the transporter more efficient.”
Promising Results in Human Brain Tissue
The team then tested the antiepileptic potential of the two molecules on samples of brain tissue obtained during surgery from 13 patients with treatment-resistant temporal lobe epilepsy.
In these slices of living tissue—collected by neurosurgeons and rapidly transported to the laboratory for electrophysiological recordings—the researchers observed that PCPZ and CLP-257 almost completely suppressed interictal spikes, the spontaneous electrical discharges that characterize the epileptic brain between seizures.
“This shows that both molecules correct the activity of epileptic networks in humans. This is a very important result, but it’s not enough,” the researcher emphasizes. “What we ultimately want to treat in patients are the seizures themselves.”
Reduced Seizures in an Animal Model
The team therefore continued its investigations in a model of chronic epilepsy. Mice that had experienced status epilepticus spontaneously develop recurrent seizures similar to those seen in patients.
When treated for several days with injections of PCPZ or CLP-290 (a derivative of CLP-257 better suited for in vivo treatment), these mice showed a reduction in seizure frequency of 40% with prochlorperazine and 55% with CLP-290.
The effects were not limited to the seizures: both molecules also reduced other electrical markers of epileptic activity, particularly high-frequency oscillations, which are considered precursors of seizures and indicators of disease severity.
Toward New Treatments
These results provide strong proof of concept: targeting KCC2 to restore chloride homeostasis in neurons represents a valid strategy for tackling drug-resistant temporal lobe epilepsy. Prochlorperazine has the advantage of already being used in human medicine for decades, and its safety profile is well documented, which could accelerate its potential repositioning as an antiepileptic treatment.
“Further research will be needed to measure the effects of these molecules on inhibitory brain function and to determine which patients might benefit from them,” concludes Jean-Christophe Poncer.
“We believe that combining KCC2 potentiators with another class of compounds—benzodiazepines, which directly strengthen inhibitory synapses—could open particularly promising therapeutic perspectives.”
For the 30% of epilepsy patients who do not respond to any treatment, these advances outline a promising new avenue, grounded in a detailed understanding of the cellular mechanisms underlying the disease.
Key Questions Answered:
A: It’s an energy problem. Pumping chloride out of cells is “expensive” for the brain (it uses a lot of ATP). When neurons are stressed by epilepsy, they stop prioritizing this pump to save energy. This causes chloride to build up inside, which effectively “flips the switch” on your brain’s brakes, making them trigger seizures instead of stopping them.
A: Yes! This is the power of “drug repurposing.” Prochlorperazine has been used for decades for nausea and migraines. This study shows it has a hidden talent: it helps stabilize the KCC2 pump. Since we already know it’s safe for humans, it could become a life-changing treatment for the 30% of epilepsy patients who don’t respond to current drugs.
A: We aren’t there yet, but it’s a massive step forward. By fixing the cellular “plumbing” of the neuron, we are treating the root cause of the seizure activity rather than just masking the symptoms. Combining this with existing drugs like benzodiazepines could create a “double-strength” brake for the brain.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychopharmacology research news
Author: Marie Simon
Source: Paris Brain Institute
Contact: Marie Simon – Paris Brain Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Enhancing KCC2 function reduces interictal activity and prevents seizures in temporal lobe epilepsy” by Florian Donneger, Adrien Zanin, Jeremy Besson, Delphine Roussel, Yoness Kadiri, Carla Pagan, Manisha Sinha, Nicolas David, Marion Russeau, Franck Bielle, Bertrand Devaux, Bertrand Mathon, Vincent Navarro, Francine Chassoux, and Jean-Christophe Poncer. PNAS
DOI:10.1073/pnas.2522722123
Abstract
Enhancing KCC2 function reduces interictal activity and prevents seizures in temporal lobe epilepsy
The neuronal K/Cl cotransporter KCC2 regulates the transmembrane chloride gradient, which controls the efficacy of GABAergic signaling.
In mesial temporal lobe epilepsy (mTLE) and other neurological disorders, reduced KCC2 expression or function can result in depolarizing GABA signaling, which is thought to contribute to pathological activity and seizures. Therefore, restoring chloride homeostasis represents a promising therapeutic strategy.
We investigated the mechanisms and antiseizure effects of two small molecules, prochlorperazine (PCPZ) and CLP-257, that have been identified as potential KCC2 enhancers. We found that both compounds enhance KCC2 function and clustering in cortical neurons while reducing its membrane diffusion, without altering canonical regulatory phosphorylation.
CLP-257 also selectively increased extrasynaptic, but not synaptic, GABAA receptor-mediated currents. Using in vitro recordings from resected brain tissue of patients with drug-resistant mTLE and in vivo recordings from a mouse model, we show that PCPZ and CLP-257 (or its prodrug CLP-290) effectively suppressed spontaneous epileptiform activity in both models.
These findings reveal that PCPZ and CLP-257 act as genuine KCC2 enhancers and provide experimental evidence of the therapeutic potential of such compounds for treating drug-resistant mTLE.
