Anakinra Reduces Epileptogenesis, Provides Neuroprotection, and Attenuates Behavioral Impairments in Rats in the Lithium-Pilocarpine Model of Epilepsy.

Alexandra V Dyomina,Alexander M Ischenko,Alexander P Schwarz,Anna A Kovalenko,Olga E Zubareva,Dmitry S Vasilev,Aleksey V Zaitsev,Maria V Zakharova,Ilya V Smolensky

doi:10.3390/ph13110340

Abstract

Temporal lobe epilepsy is a widespread chronic disorder that manifests as spontaneous seizures and is often characterized by refractoriness to drug treatment. Temporal lobe epilepsy can be caused by a primary brain injury; therefore, the prevention of epileptogenesis after a primary event is considered one of the best treatment options. However, a preventive treatment for epilepsy still does not exist. Neuroinflammation is directly involved in epileptogenesis and neurodegeneration, leading to the epileptic condition and cognitive decline. In the present study, we aimed to clarify the effect of treatment with a recombinant form of the Interleukin-1 receptor antagonist (anakinra) on epileptogenesis and behavioral impairments in rats using the lithium–pilocarpine model. We found that anakinra administration during the latent phase of the model significantly suppressed the duration and frequency of spontaneous recurrent seizures in the chronic phase. Moreover, anakinra administration prevented some behavioral impairments, including motor hyperactivity and disturbances in social interactions, during both the latent and chronic periods. Histological analysis revealed that anakinra administration decreased neuronal loss in the CA1 and CA3 areas of the hippocampus but did not prevent astro- and microgliosis. The treatment increased the expression level of the solute carrier family 1 member 2 gene (Slc1a2, encoding excitatory amino acid transporter 2 (EAAT2)) in the hippocampus, potentially leading to a neuroprotective effect. However, the increased gene expression of proinflammatory cytokine genes (Interleukin-1β (Il1b) and tumor necrosis factor α (Tnfa)) and astroglial marker genes (glial fibrillary acidic protein (Gfap) and inositol 1,4,5-trisphosphate receptor type 2 (Itpr2)) in experimental rats was not affected by anakinra treatment. Thus, our data demonstrate that the administration of anakinra during epileptogenesis has some beneficial disease-modifying effects.

Highlights

Epilepsy is a widespread chronic disorder that manifests as spontaneous seizures [1]
The present study aims to clarify the effect of anakinra treatment on epileptogenesis and comorbid behavioral impairments in rats using the lithium–pilocarpine model
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Summary

Introduction

Epilepsy is a widespread chronic disorder that manifests as spontaneous seizures [1]. Progressive epilepsy becomes refractory, and nearly 30% of cases do not respond to drug therapy [3]. Traumatic factors (infections and injuries), tumors, status epilepticus (SE), and perinatal complications can frequently cause acquired epilepsy [5]. In these cases, seizures usually develop after a latent period. Antiepileptogenic therapy during the latent period is considered the best option to prevent epilepsy [6,7]. The development of rational preventive therapy requires knowledge of the exact mechanisms of epileptogenesis. Anti-inflammatory therapy in susceptible groups could reduce the risk of the development of epilepsy

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