Effects of dexamethasone on the Li-pilocarpine model of epilepsy: protection against hippocampal inflammation and astrogliosis

Abstract

BackgroundTemporal lobe epilepsy (TLE) is the most common form of partial epilepsy and is accompanied, in one third of cases, by resistance to antiepileptic drugs (AED). Most AED target neuronal activity modulated by ionic channels, and the steroid sensitivity of these channels has supported the use of corticosteroids as adjunctives to AED. Assuming the importance of astrocytes in neuronal activity, we investigated inflammatory and astroglial markers in the hippocampus, a key structure affected in TLE and in the Li-pilocarpine model of epilepsy.MethodsInitially, hippocampal slices were obtained from sham rats and rats subjected to the Li-pilocarpine model of epilepsy, at 1, 14, and 56 days after status epilepticus (SE), which correspond to the acute, silent, and chronic phases. Dexamethasone was added to the incubation medium to evaluate the secretion of S100B, an astrocyte-derived protein widely used as a marker of brain injury. In the second set of experiments, we evaluated the in vivo effect of dexamethasone, administrated at 2 days after SE, on hippocampal inflammatory (COX-1/2, PGE2, and cytokines) and astroglial parameters: GFAP, S100B, glutamine synthetase (GS) and water (AQP-4), and K+ (Kir 4.1) channels.ResultsBasal S100B secretion and S100B secretion in high-K+ medium did not differ at 1, 14, and 56 days for the hippocampal slices from epileptic rats, in contrast to sham animal slices, where high-K+ medium decreased S100B secretion. Dexamethasone addition to the incubation medium per se induced a decrease in S100B secretion in sham and epileptic rats (1 and 56 days after SE induction). Following in vivo dexamethasone administration, inflammatory improvements were observed, astrogliosis was prevented (based on GFAP and S100B content), and astroglial dysfunction was partially abrogated (based on Kir 4.1 protein and GSH content). The GS decrease was not prevented by dexamethasone, and AQP-4 was not altered in this epileptic model.ConclusionsChanges in astroglial parameters emphasize the importance of these cells for understanding alterations and mechanisms of epileptic disorders in this model. In vivo dexamethasone administration prevented most of the parameters analyzed, reinforcing the importance of anti-inflammatory steroid therapy in the Li-pilocarpine model and possibly in other epileptic conditions in which neuroinflammation is present.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1109-5) contains supplementary material, which is available to authorized users.

Traumatic brain injury induces long-lasting changes in immune and regenerative signaling

“…There is an important therapeutic implication here; evidence of a protective, regenerative response at all post-injury intervals indicates that therapies augmenting these responses may be beneficial regardless of how many months or years have passed since the initial TBI. For instance, since steroid-induced decreases in S100b levels have been shown to reduce inflammation in the hippocampus in a rat model of epilepsy, the significant decrease in expression of S100b at one year post-TBI would protect against inflammation [73]. The increased expression of Atf3 also appears to be a protective response (see Fig 6); a recent study found that neuroinflammation was enhanced in Atf3 knockout mice after TBI [74].…”

Effects of Dexamethasone on Remodeling of the Hippocampal Synaptic Filamentous Actin Cytoskeleton in a Model of Pilocarpine-induced Status Epilepticus

“…Numerous studies have focused on the effects of glucocorticoids in epilepsy and convulsions, but the conclusions are controversial so far [11,12,[28][29][30][31][32][33]. Different dosages, courses, and time points of glucocorticoid administration might be responsible for these discrepancies.…”

“…Glucocorticoids have proven to be helpful in treatment of epilepsy in numerous clinical and experimental studies [8][9][10][11][12]. Glucocorticoids have two type of receptors in vivo: mineralocorticoid receptors (MRs) of high affinity and glucocorticoid receptors (GRs) of low affinity [13].…”

Targeting S100B Protein as a Surrogate Biomarker and its Role in Various Neurological Disorders

“…Epilepsy is a neurological disorder characterized by recurrent and spontaneous seizures caused by excessive, abnormal, and hypersynchronous neuronal discharge [ 106 ]. An imbalance between the excitatory glutamatergic and inhibitory GABAergic neuronal discharges causes brain damage and cell loss [ 107 ]. Astrocytes, a subtype of glial cells, play an important role in regulating cerebral ion homeostasis, transmitter regulation, maintenance of the blood-brain barrier (BBB), and structural, as well as metabolic support of neuronal cells.…”