Etanercept rescues cognitive deficits, depression-like symptoms, and spike-wave discharge incidence in WAG/Rij rat model of absence epilepsy

doi:10.1016/j.yebeh.2020.107532

Epilepsy & Behavior

Volume 115, February 2021, 107532

https://doi.org/10.1016/j.yebeh.2020.107532 Get rights and content

Highlights

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Memory impairment and depression-like behaviors were observed in 8-month-old WAG/Rij rats.
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TNF alpha inhibition by etanercept rescued these impairments.
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Etanercept decreased the number of seizures without changing the seizure duration in WAG/Rij rats.

Abstract

Pro-inflammatory cytokines have been shown to be associated with the development of seizures in the WAG/Rij rat model of absence epilepsy. Importantly, WAG/Rij rats also exhibit cognitive deficits and depression-like behaviors. It is possible that pro-inflammatory cytokines mediate these comorbid conditions of absence epilepsy given their well-established effects on cognition and affective responses. The current study investigated the potential therapeutic effect of etanercept (tumor necrosis factor inhibitor) on cognitive impairment, depression-like behavior, and spike-wave discharges (SWDs) typically observed in the WAG/Rij rats. Eight-month-old male WAG/Rij rats and Wistar controls were tested in Morris water maze (MWM), passive avoidance (PA), forced swimming, sucrose preference, and locomotor activity tests, and electroencephalogram (EEG) recordings were taken from a separate group of WAG/Rij rats after 8 weeks of etanercept or vehicle treatment. Consistent with earlier work, WAG/Rij rats exhibited cognitive deficits and depression-like behavior. From these, the cognitive deficits and despair-like behavior were rescued by etanercept administration, which also reduced the frequency of SWDs without affecting their duration. Our results support the hypothesis that pro-inflammatory cytokines mediate the absence seizures and comorbid symptoms of absence epilepsy.

Introduction

Clinical observations suggest that behavioral, cognitive, and affective disorders commonly accompany epilepsy [1]. The set of symptoms associated with these comorbid conditions occur in different epilepsies with various etiological, neuroanatomical, and pharmacological features [2]. Preclinical and clinical studies investigate shared mechanisms to prevent and manage concomitant diseases in epilepsy. To this end, animal models of epilepsy serve as valuable subjects. WAG/Rij strain of rats, one of the most utilized genetic rat models of absence epilepsy, also exhibits the comorbidity profile observed in the person with epilepsy (PWE). For instance, depression-like behaviors were reported in WAG/Rij rats; based on this finding WAG/Rij strain was argued to serve as a genetic animal model of absence epilepsy with comorbidity of depression [3]. Similar results were also reported in other rat strains that display spike-wave discharge (SWD) activity [4]. In addition to depression-like behavior, a number of studies have shown that absence epilepsy is associated with cognitive impairments [5] which has also been confirmed in the WAG/Rij rats [6], [7], [8].

Given the fact that it plays a role in the etiopathogenesis of multiple neurological and psychiatric disorders including epilepsy, depression, and cognitive impairment, inflammation may also constitute a common mechanism for the comorbid disorders in epilepsy. A number of studies support this possibility. Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that is released by microglia and astrocytes in the nervous system regulates neuronal excitation via various mechanisms [9], [10], [11], [12] such as augmentation of glutamatergic transmission via the upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and glutamate synthesis while attenuation of gamma aminobutyric acid (GABA)-ergic transmission via induction of endocytosis of GABA_A-R [9], [10]. For instance, this mechanism along with other pro-inflammatory cytokine-mediated changes in brain functions has been implicated in epileptogenesis [13]. Proinflammatory cytokines have also been shown to stimulate ictogenesis in WAG/Rij rats [14]. There is now also a considerable amount of evidence that shows the antidepressant and cognitive enhancing property of the TNF-α inhibitors (etanercept and infliximab) in different depression and cognitive decline models including acute and chronic mild stress [15], [16], [17], streptozotocin-induced diabetes [18], and aging [19].

It is possible that pro-inflammatory cytokines mediate the cognitive impairments and depression-like behaviors associated with absence epilepsy. In light of these findings and given the cognitive impairments and depression-like behavior observed in WAG/Rij rat model of absence epilepsy, the current study investigated the potential therapeutic effect of etanercept (a fusion protein functioning as a decoy receptor) on cognitive impairment, depression-like behavior, and SWDs in the WAG/Rij rats.

Section snippets

Materials and methods

Six-month-old male albino Wistar and WAG/Rij rats (Kocaeli University, Experimental Medical Research and Application Center, Kocaeli, Turkey) that weighed 300–400 g were tested in this study. Animals were housed under a 12-h light/dark cycle and had ad libitum access to water and food (except for 23-h deprivation prior to sucrose preference test (SPT)). Experiments were performed during the light cycle. All animals were naive to the experimental procedures. Animals tested in behavioral

Escape latency

The escape latencies were analyzed with a3-way mixed-design analysis of variance (ANOVA) where training day was included as the within-subject factor and genotype and drug condition were included as between-subject factors. As expected, our analysis showed that escape latencies decreased significantly over the course of training, F(3,108) = 29.79, p < 0.0001, η_p² = 0.453 (Fig. 1A). Furthermore, the effect of genotype (F(1,36) = 24.35, p < 0.0001, η_p² = 0.403; WAG/Rij > Wistar) was significant.

Discussion

The clinical observations point at comorbidities of absence epilepsy that includes cognitive impairment and depression-like behavior [2], [5]. Consistent with this observation, depression-like behaviors, and although to a lesser extent cognitive deficits, have also been reported in the WAG/Rij rat and Genetic Absence Epilepsy Rats from Strasbourg (GAERS) models of absence epilepsy [3], [6], [20], [21]. Importantly, inflammation and proinflammatory cytokines have been shown to have a possible

Funding and disclosure

This research was supported by grants from the Scientific Research Projects Coordination Unit of Kocaeli University (Project number: KOU BAP 2016/33). The authors declare no conflict of interest.