Summary: The brain maintains calm through an inhibitory “braking system” known as GABAergic signaling. In temporal lobe epilepsy, this brake can fail because neurons accumulate too much chloride: GABA switches from an inhibitor into an excitatory trigger, promoting seizures.
A new study identifies two molecules—prochlorperazine (PCPZ) and CLP-257—that restore this balance. By stabilizing the key chloride transporter KCC2 on the neuronal membrane, these compounds recover inhibitory signaling. Notably, the treatment nearly eliminated abnormal electrical discharges in human epileptic tissue and reduced seizure frequency by up to 55% in animal models.
Key Facts
- KCC2 dysfunction: KCC2 normally pumps chloride out of neurons. When it fails, GABAergic signaling can depolarize neurons instead of inhibiting them, promoting epileptic activity.
- Spatial stabilization: The molecules do not simply increase KCC2 quantity; they cause the transporter to cluster into dense, efficient patches at the cell surface.
- Human tissue validation: In living brain slices from 13 patients with drug-resistant temporal lobe epilepsy, both compounds almost completely suppressed spontaneous interictal spikes.
- Seizure reduction in vivo: In a chronic mouse epilepsy model, prochlorperazine reduced seizure frequency by about 40%, while CLP-290 (a prodrug of CLP-257 suited for in vivo use) reduced seizures by about 55%.
- Repurposing advantage: Prochlorperazine is an FDA-approved antipsychotic and anti-nausea drug with a known safety profile, which could accelerate clinical testing for epilepsy.
Source: Paris Brain Institute
For normal brain function, electrical activity must be tightly regulated. A principal mechanism is GABAergic inhibition, which prevents runaway excitability and the bursts that define seizures. This inhibitory system depends on a delicate intracellular chloride balance.
The K+/Cl− cotransporter KCC2 maintains low intracellular chloride by extruding it from neurons. When KCC2 function is reduced—as commonly observed in mesial temporal lobe epilepsy (mTLE) and other neurological disorders—chloride accumulates and GABAergic signals can become depolarizing rather than inhibitory.
“Continuously pumping chloride out of neurons consumes a lot of ATP, the cell’s energy currency. Under metabolic stress, neurons may deprioritize this process to conserve energy,” explains Jean‑Christophe Poncer, co-leader of the EpiC team at the Paris Brain Institute. “As a result, KCC2 activity is markedly reduced in epilepsy. Our goal was to find a way to restore it.”
Two molecules that strengthen a failing transporter
High-throughput screening previously flagged two small molecules—prochlorperazine (PCPZ) and CLP-257—as capable of restoring chloride balance in neurons. Prochlorperazine is a long-established antipsychotic and antiemetic used for nausea, migraines, and some psychiatric conditions. CLP-257 has been explored in neuropathic pain research. Their potential as antiseizure agents had not been fully tested.
In cultured rat hippocampal neurons, Poncer’s team showed that both compounds significantly improved KCC2 function by restoring the chloride gradient, allowing GABAergic signaling to regain inhibitory potency.
So how do these drugs act? “Rather than increasing total KCC2 levels, PCPZ and CLP-257 alter how the transporter is organized on the cell surface,” Poncer says. “They promote clustering of KCC2 into dense membrane patches and reduce its lateral diffusion. This spatial stabilization enhances transporter efficiency.”
Evidence from human epileptic brain tissue
To test translational potential, the researchers examined live cortical tissue removed from 13 patients undergoing surgery for treatment-resistant mTLE. In electrophysiological recordings from these slices, PCPZ and CLP-257 nearly abolished interictal spikes—the spontaneous discharges that occur between seizures.
“These findings demonstrate that both compounds correct pathological network activity in human epileptic tissue,” Poncer notes. “It’s a crucial milestone, but the objective remains to suppress clinical seizures in patients.”
Seizure suppression in a chronic epilepsy model
The team tested the compounds in mice that develop chronic recurrent seizures following status epilepticus, a model that mirrors human chronic epilepsy. Daily injections of PCPZ or CLP-290 (a bioavailable derivative of CLP-257) for several days reduced seizure frequency—by roughly 40% with prochlorperazine and about 55% with CLP-290.
Beyond lowering seizure counts, both treatments diminished other electrophysiological markers of epileptic pathology, including high-frequency oscillations that often precede seizures and reflect disease severity.
Toward new treatment strategies
These experiments provide strong proof of concept that enhancing KCC2 function to restore chloride homeostasis is a viable strategy for drug-resistant temporal lobe epilepsy. The fact that prochlorperazine is already used clinically and has an established safety profile could speed efforts to repurpose it as an antiepileptic.
“Further work is needed to characterize how these compounds influence inhibitory network function and to identify which patients may benefit most,” says Poncer. “We also think combining KCC2 enhancers with existing drugs such as benzodiazepines—which strengthen inhibitory synapses directly—may deliver particularly effective therapeutic outcomes.”
For the roughly 30% of people with epilepsy who do not respond to current medications, this approach offers a mechanistic, targeted avenue for new therapies grounded in cellular physiology.
Key Questions Answered:
A: It is primarily an energy issue. Extruding chloride is metabolically costly, so under stress neurons may reduce KCC2 activity to conserve ATP. This allows chloride to accumulate inside cells, which can flip inhibitory GABA signals into excitatory ones and promote seizures.
A: Potentially, yes. Prochlorperazine has a long clinical track record and a known safety profile. This study shows it can stabilize KCC2 clustering and restore inhibitory signaling in epileptic tissue, supporting the idea of drug repurposing for patients who don’t respond to current antiepileptic drugs.
A: Not yet. These results represent a significant advance toward treating the cellular cause of seizures rather than only alleviating symptoms. More research and clinical testing are required to assess long-term efficacy and patient selection. Combining KCC2 enhancers with other therapies could yield improved outcomes.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by the editorial 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 controls the transmembrane chloride gradient that determines GABAergic signaling efficacy. In mesial temporal lobe epilepsy and other disorders, reduced KCC2 expression or function can lead to depolarizing GABA responses that contribute to pathological activity and seizures. Restoring chloride homeostasis is therefore a promising therapeutic avenue.
The authors investigated the mechanisms and antiseizure effects of two small molecules, prochlorperazine (PCPZ) and CLP-257, which had been proposed as KCC2 enhancers. Both compounds increased KCC2 function and promoted transporter clustering in cortical neurons while reducing membrane diffusion, without changing established regulatory phosphorylation patterns.
CLP-257 also selectively enhanced extrasynaptic GABA_A receptor–mediated currents. Using electrophysiological recordings from resected tissue of patients with drug-resistant mTLE and in vivo recordings from a mouse model, the study shows that PCPZ and CLP-257 (and the prodrug CLP-290) effectively suppressed spontaneous epileptiform activity in both settings.
These findings identify PCPZ and CLP-257 as genuine KCC2 enhancers and provide experimental evidence for the therapeutic potential of targeting KCC2 in drug-resistant temporal lobe epilepsy.