2026 ECNP Congress

PS03-3014

Long-term Perampanel treatment during epileptogenesis attenuates cognitive impairment and regulates hippocampal Neurokinin B expression in a rat model of epilepsy

Mihaela Shishmanova-Doseva — D. Barbutska, Y. Koeva, K. Saracheva · Medical University of Plovdiv, Department of Pharmacology Toxicology and Pharmacotherapy, Plovdiv, Bulgaria

2026 ECNP Congress

Purpose

Patients with epilepsy, especially those with temporal lobe epilepsy (TLE), may experience a heightened risk of developing cognitive impairment and mood changes over time. These problems can be further compounded by the adverse side effects of some antiepileptic drugs [1]. Perampanel (PRM) is a third-line drug whose mode of action is unique among anti-seizure medications [2]. Perampanel acts as a selective, non-competitive antagonist of AMPA receptors within the central nervous system. Inhibiting these glutamate receptors serves to curtail excitatory neurotransmission, diminish neuronal excitability and circumscribe the propagation of epileptic discharges. This provides effective seizure control [3]. The present study aimed to evaluate the effects of perampanel treatment on the pathogenesis of comorbid cognitive impairments, as well as the underlying mechanisms of these effects in a rat pilocarpine-induced post-status epilepticus (SE) model of TLE.

Methods

Male Wistar rats were randomly divided into four groups: C-veh, SE-veh, C-PRM and SE-PRM. SE was induced in half of the animals by a single intraperitoneal injection of LiCl (127 mg/kg), followed by an intraperitoneal injection of pilocarpine (30 mg/kg) 24 hours later. Three hours after SE onset perampanel was administered orally by gavage for 12 weeks. Matched groups were treated with vehicle. Eight weeks after LiCl/pilocarpine injection, all rats were subjected to a battery of tests. Activity cage and step-down tests were performed. Following the final test, the animals were decapitated, and their brains were collected for further immunohistochemical analysis. Statistical evaluation was carried out by two-way ANOVA and Tukey post-hoc test, at a level of significance of p<0.05.

Results

The post-hoc test revealed that the SE-PRM group exerted a beneficial effect on hyperactivity with fewer horizontal movements compared to the SE-veh group (p < 0.05) while no effect on vertical movements was observed. PRM treatment during epileptogenesis demonstrated beneficial effect on epilepsy-induced impairment of hippocampus-dependent passive learning and memory in the step-down test. The SE-PRM group showed significantly longer time for staying on the platform compared to the epileptic group (p < 0.05) during both learning and memory sessions while C-PRM animals had comparable with the control group results (p > 0.05 vs C-veh). Post-hoc analysis showed that the SE-veh group led to significantly higher expression of Neurokinin B in the hippocampus compared to the control animals (p < 0.05) whereas the SE-PRM animals exhibited significantly lower expression of the neuropeptide compared to the SE-veh group (p < 0.001). Moreover, C-PRM rats show no changes in the expression of Neurokinin B in comparison with control animals (p > 0.05).

Conclusions

Long-term treatment with perampanel during epileptogenesis managed to diminish the negative influence of epilepsy and facilitate memory consolidation and retrieval. Decrease in hyperactivity by perampanel treatment was also observed during the chronic state of TLE. Furthermore, the drug reduced the hippocampal expression on Neurokinin B which plays a crucial role in modulating neuronal excitability and neurotransmitter release in the glutamatergic system. Thus, perampanel modulates a key pathophysiological mechanism implicated in epileptogenesis, thereby exerting an indirect positive effect on cognitive function.

References

  1. Novak A, Vizjak K, Rakusa M. Cognitive Impairment in People with Epilepsy. J Clin Med. 2022 5;11(1):267. doi: 10.3390/jcm11010267. PMID: 35012007; PMCID: PMC8746065.
  2. Tsai JJ, Wu T, Leung H, Desudchit T, Tiamkao S, Lim KS, Dash A. Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings. Acta Neurol Scand. 2018 Apr;137(4):378-391. doi: 10.1111/ane.12879. Epub 2017 Dec 7. PMID: 29214650.
  3. Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand Suppl. 2013;(197):19-24. doi: 10.1111/ane.12100. PMID: 23480152; PMCID: PMC4506647.