Cytokines and Absence Seizures in a Genetic Rat Model

Abstract

We investigated the role of two cytokines, IL-1β and TNF-α, in the development of absence seizures using a genetic model of absence epilepsy in WAG/Rij rats. We administered these cytokines to animals systemically and measured the number of spike-wave discharges (SWDs) in the EEG. We also coadministered IL-1β with the GABA reuptake inhibitor tiagabine and measured the levels of IL-1β and TNF-α in the brain and blood plasma of 2-, 4-, and 6-month-old WAG/Rij rats and animals that served as a non-epileptic control (ACI). We found that IL-1β induced a significant increase in SWDs 2-5 h after administration, while TNF-α enhanced SWDs much later. Both cytokines enhanced passive behavior; body temperature was elevated only after TNF-α. The action of tiagabine was potentiated by earlier IL-1β injection, even when IL-1β was no longer active. Young WAG/Rij rats showed higher levels of TNF-α in blood serum than young ACI rats; the effects in the brain tended to be opposite. The marked differences in timing of the increase in SWDs suggest different time scales for the action of both cytokines tested. It is proposed that the results found after TNF-α are due to the de novo synthesis of IL-1β. TNF-α may possess neuroprotective effects. IL-1β might increase GABAergic neurotransmission. The changes in the efficacy of antiepileptic drugs related to changes in the cytokine systems may have some clinical relevance.

Lipopolysaccharide induced increase in seizure activity in two animal models of absence epilepsy WAG/Rij and GAERS rats and Long Evans rats

“…Thus, explanation of LPS evoked small differences in the time course of LPS evoked effects on SWD number and body temperature among the three rat strains is not straightforward. However, it was demonstrated that the LPS evoked increase in pro-inflammatory cytokines can increase absence epileptic activity between 30 and 270 min after injection independently from inflammation induced body temperature changes (Kovács et al, 2006(Kovács et al, , 2011, in which IL-1␤ may be one of the main pro-epileptic (pro-absence) mediators possibly via GABAergic neurotransmission (Van Luijtelaar et al, 2012) in WAG/Rij animals. Nevertheless, the presence of reactive astrocytes in the GAERS cortex and thalamus before the onset of absence epileptic seizures (Dutuit et al, 2000) and IL-1␤ induction in reactive astrocytes of adult GAERS rat somatosensory cortex at the onset of SWDs and the contribution of IL-1␤ to SWD occurrence were also demonstrated in GAERS rats (Akin et al, 2011).…”

“…Indeed, pro-inflammatory cytokines (e.g., interleukin-1 ␤ (IL-1␤) and tumor necrosis factor-␣ (TNF-␣)) synthesized by glial cells in the central nervous system (CNS) elevate neuronal excitability (Rodgers et al, 2009;Vezzani et al, 2008;Vezzani and Granata, 2005). Changes in IL-1␤ and TNF-␣ levels may have a role in SWD generation/precipitation in two animal models of human absence epilepsy, GAERS rats and WAG/Rij rats (Akin et al, 2011;Van Luijtelaar et al, 2012). Lipopolysaccharide evokes rapid excitation in the cortex (Wang and White, 1999), enhances seizure susceptibility (Sayyah et al, 2003), increases absence epileptic activity and body temperature (Kovács et al, 2006(Kovács et al, , 2011 brain (Györffy et al, 2014).…”

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

“…Accordingly, based on this background, it is not possible to exclude that fingolimod can exert antiepileptogenic effects in this strain through some kind of antiinflammatory mechanisms, which could also be linked to a modulation of neuronal S1P receptors [13]. It is known that glial activation and the related overexpression of proinflammatory cytokines seem to play a crucial role in epileptogenesis both in humans and in several animal models of epilepsy [58][59][60][61]; however, to date, such a relationship between neuroinflammation and absence seizure development in WAG/Rij rats remains unclear [27,28]. Indeed, neuroinflammation and related mediators worsen absence seizures in this strain [28-30, 62, 63], while cyclooxygenase inhibitors have some partial antiabsence properties [11,63,64] and etoricoxib, a selective COX-2 inhibitor, also possesses antiepileptogenic effects in this strain, which appear to be more effective than fingolimod with a reduction in the development of absence seizures of about 45% vs 30% obtained with fingolimod [11].…”

“…etoricoxib, indomethacin and rapamycin) acting on inflammation can both reduce absence seizures and their development and accordingly, increasing neuroinflammation increases absence seizures 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 [11,[29][30][31]. The role of inflammatory cytokines have been previously studied by Van Luijtelaar et al [28], IL-1beta and TNF-alpha administration can both increase absence seizures in this model while their levels were found to be altered in the blood and/or the brain of WAG/Rij rats at some ages with no clear correlation with SWDs development concluding therefore that a possible modulatory effect of neuroinflammation is plausible but TNF-alpha might not have necessarily a negative impact as also suggested by some other previous articles in other models [32]. Furthermore, considering the likely role of the mTOR pathway and HDAC in the etiopathogenesis of idiopathic and acquired epilepsy syndromes and fingolimod mechanism of action [33][34][35], we have also explored a potential effect of fingolimod on these targets in this rat strain.…”

“…Considering fingolimod potential effects in epilepsy/epileptogenesis and the lack of data on genetic epilepsy models and epilepsy comorbidities, we aimed in the present study, to evaluate the effects of some fingolimod treatments (acute, sub-chronic and early long-term treatment) in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity (dysthymia and decline in learning and memory performance) [25][26][27]. Despite in this latter model neuroinflamamtion does not seem to play a major role [28]; it has been demonstrated that drugs (e.g. etoricoxib, indomethacin and rapamycin) acting on inflammation can both reduce absence seizures and their development and accordingly, increasing neuroinflammation increases absence seizures 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 [11,[29][30][31].…”