Chemokine (CXC motif) ligand 8 (CXCL8) is a pro-inflammatory chemokine binding to CXC motif receptors 1/2 (CXCR1/2). Patients with temporal lobe epilepsy (TLE) exhibit increased serum CXCL8 levels. CXC motif ligand 1 (CXCL1), a murine ortholog of CXCL8, has been implicated in seizure generation and neuronal loss. This study evaluated the antiepileptogenic and antiseizure effects of reparixin in amygdaloid kindling rat model of TLE. Reparixin was administered during the kindling period for 14 days, and seizures were induced twice daily via electrical stimulation. To assess the antiseizure effects, reparixin was administered to fully kindled animals, and stimulations were performed 24 and 48 h later. Levetiracetam, a broad-spectrum antiseizure drug, was administered intraperitoneally (i.p.) as positive control 1 h before each stimulation. Reparixin delayed secondary seizure generalization during kindling. Reparixin reduced seizure severity and after-discharge duration in fully kindled animals at 24 h from treatment initiation. CXCR1/2 and protein kinase B pathway proteins exhibited no significant changes; reparixin reduced the phospho-extracellular signal-regulated kinase (pERK)/ERK ratio in the cortex and hippocampus. CXCL1 expression was significantly decreased in the cortex. Reparixin exhibited antiepileptogenic and partial antiseizure effects by modulating the CXCL1–CXCR1/2 axis and reducing ERK signaling. Already in clinical trials on respiratory diseases, reparixin could be repurposed for epilepsy therapy.

Chemokine (CXC motif) ligand 8 (CXCL8) is a pro-inflammatory chemokine binding to CXCR1/2 receptors, is elevated in the serum of patients with Temporal Lobe Epilepsy (TLE). Its murine ortholog CXCL1, is implicated in seizure generation and neuronal loss. This study evaluates the anti-epileptogenic and anti-seizure effect of reparixin, an allosteric CXCR1/2 antagonist in amygdaloid kindling rat model of TLE. Reparixin was administered via osmotic pumps (8mg/kg/h) during kindling period over 14 days and seizures induced twice daily by electrical stimulation. To asses anti-seizure effects, fully kindled animals reparixin was given before stimulations at 24 and 48 hours post-implantation. Brain tissue was analyzed for CXCL1-CXCR1/2 axis activation. Reparixin delayed secondary seizure generalization during kindling.. While it did not completely prevent kindling, reparixin reduced seizure severity and after-discharge duration in fully kindled animals at 24 hours post-treatment. CXCR1/2 and AKT pathway proteins showed no significant changes, reparixin reduced the phospho-ERK:ERK ratio in the cortex and hippocampus. CXCL1 expression was also significantly decreased in the cortex. Reparixin exhibits anti-epileptogenic and partial anti-seizure effects by modulating the CXCL1-CXCR1/2 axis and reducing ERKsignalling, underscoring its potential as a neuroinflammation-targeting epilepsy treatment. Already in clinical trials for respiratory diseases, reparixin could be repurposed for epilepsy therapy.

Aims: Absence seizures, characterized by spike‐and‐wave discharges (SWDs), are mediated by reciprocal thalamocortical interactions; however, the contribution of developing inhibitory networks to SWDs remains unclear. We investigated the developmental trajectory of inhibitory interneurons in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) by analyzing their distribution across postnatal development in the somatosensory (S1) and motor (M1) cortices, the hippocampus, and striatum. Methods: The neurodevelopmental trajectory of parvalbumin‐positive (PV+) and somatostatin‐positive (SST+) interneurons was quantified at three critical stages: postnatal day 14 (P14), when SWDs were not yet observed, P21 when immature SWDs appear, and adulthood (P90), when mature SWDs are established. Wistar rats served as controls. Brain sections were processed immunohistochemically to quantify interneuron density. Results: PV+ interneuron density across S1 and M1 was significantly higher in GAERS at P14 than control. However, this difference was not maintained at P21 and adults. Conversely, SST+ interneurons exhibited a delayed increase in M1. GAERS displayed higher PV+ interneuron density in the dentate gyrus and CA1 at P14, whereas SST+ interneuron density remained unchanged across hippocampal subfields. Striatal PV+ and SST+ interneurons increased at later developmental stages, suggesting altered inhibition in basal ganglia. Conclusion: These findings demonstrate a temporally dynamic and region‐specific reorganization of interneurons in GAERS that may underlie absence epileptogenesis.