Pathogenesis Of Status Epilepticus Research Articles

The Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score Predicts the Prognosis of Adults with Status Epilepticus: A Retrospective Study.

The hemoglobin, albumin, lymphocyte, and platelet (HALP) score has been indicated to be a novel indicator that reflects systemic inflammation and is associated with the functional outcome in various neurological diseases. Since inflammation is closely involved in the pathogenesis of status epilepticus (SE), this study aimed to explore the predictive value of HALP for the prognosis of SE patients. In the retrospective study, we investigated and validated the predictive value of HALP for the prognosis of adult SE patients. We collected patient's clinical characteristics and laboratory test data. Information of 30-day mortality after SE onset was obtained, and modified Rankin scale (mRS) scores were used to evaluate the clinical outcomes. Multivariable logistic regression models were applied to explore the association between HALP and SE prognosis. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff of HALP to predict 30-day mortality in SE patients. We first analyzed the discovery cohort of 116 patients with SE. We observed that 19.0% (22/116) of the patients died within 30 days after SE onset, and 26.3% (20/76) had poor outcomes during the 6-month follow-up. Multivariate logistic regression analysis indicated that lower HALP on admission was an independent predictor of 30-day mortality (odds ratio: 0.980; 95% confidence interval, 0.962-0.999; P = 0.044). In ROC analysis, a HALP of 20.32 was identified as the optimal cutoff value to predict 30-day mortality in SE patients. Furthermore, multivariate logistic regression analysis showed that HALP < 20.32 was related to an increased risk of poor SE outcomes (odds ratio: 27.051; 95% confidence interval, 3.589-203.909; P = 0.001), which was validated in the external cohort. Lower HALP is independently associated with an increased risk of 30-day mortality and poor functional outcomes in patients with SE. Our findings suggest that HALP may be a promising biomarker for predicting SE prognosis.

Role of High Mobility Group Box-1 in Status Epilepticus, From Pathophysiology to Biomarker and Therapeutic Potential

Status epilepticus (SE) is a neurological emergency that require prompt diagnostic and treatment measures due to its associated mortality and morbidity. The role of neuro-inflammation in status epilepticus has been studied extensively and many potential molecules have been proposed as a promising biomarkers and therapeutic targets for the condition. Inside the nucleus, HMGB1 is a DNA-binding protein with many housekeeping functions. Under certain conditions, HMGB1 will be translocated to the extracellular space promoting a strong pro-inflammatory reaction with activation of many downstream inflammatory pathways related to seizure onset and progression. In this review the potential role of HMGB1 in the pathogenesis of SE was highlighted stressing on the promising implications of this molecule as a therapeutic target for SE.

Long non-coding RNA Tug1 regulates inflammation in microglia and in status epilepticus rats through the NF-κB signaling pathway

BackgroundInflammation plays an important role in the pathogenesis of status epilepticus (SE). The long non-coding RNA (lncRNA) taurine up-regulated gene1 (Tug1) plays a well-defined role in inflammatory diseases. However, the molecular mechanism of Tug1 in SE progression remains unknown. In present study, we investigated whether Tug1 is involved in microglial inflammation in SE rats.MethodsThe SE rat model was established via intraperitoneal injection of lithium chloride-pilocarpine. RNA-binding protein immunoprecipitation (RIP) and RIP sequencing were carried out in rat microglia (RM). Tug1 cloned into the adenovirus was overexpressed in the microglia. Knockdown of Tug1 was performed via siRNA transfection. The level of Tug1 and inflammatory factors IL-1β and TNF-α was examined by real-time polymerase chain reaction (RT-PCR) and western blotting. Protein levels of p65, p-p65, p-ΙκΒα and ΙκΒα were assessed by western blotting.ResultsThe RIP-seq result showed 14 lncRNAs that bound to the NF-κB p65 protein in RM. The lncRNA Tug1 directly interacted with p65. The level of declined Tug1 was decreased in the hippocampus of SE rats. Overexpression of Tug1 reduced the LPS-induced inflammation and M1/M2 polarization of microglia, while knockdown of Tug1 aggravated the inflammatory response in microglia. Accordingly, the protein levels of p-p65/p65 and p-ΙκΒα/ΙκΒα were reduced in the Tug1-overexpression microglia and elevated in the Tug1-knockdown microglia.ConclusionsThese findings indicate that Tug1 modulates the inflammation in microglia through the NF-κB signal pathway, and the Tug1/P65 axis are like to play a significant role in the inflammatory processes, providing a valid target for the therapy of SE.

LncRNA Snhg5 Attenuates Status Epilepticus Induced Inflammation through Regulating NF-κΒ Signaling Pathway.

Status epilepticus (SE) induced inflammation plays an important role in the pathogenesis of SE. Long non-coding RNA small nucleolar RNA host gene 5 (lncRNA Snhg5) has been reported in various inflammatory diseases. However, the mechanism of Snhg5 regulated inflammation in SE remains unclear. Therefore, this study aimed to clarify the role and mechanism of Snhg5 in SE-induced inflammation in vitro and vivo. In vitro, lipopolysaccharide (LPS)-induced inflammation in microglia was used to mimic the inflammation after SE. In vivo, SE model was induced by lithium chloride and pilocarpine. The level of Snhg5, p65, p-p65, p-inhibitor of kappaB (IκB)α, IκBα and inflammatory factors (tumor necrosis factor (TNF)-α, interleukin (IL)-1β) were measured via quantitative real-time PCR or Western blot. The Nissl stain and immunohistochemical stain were performed to observe hippocampal damage and microglia proliferation. The results showed Snhg5 was up-regulated in the rat and microglia. Knockdown of Snhg5 inhibited LPS-induced inflammation and relative expression of p-65/p65, p-IκBα/IκBα. Moreover, down-regulation of Snhg5 attenuated SE-induced inflammation and reduced the number of microglia in hippocampus. These findings indicated that Snhg5 modulates the inflammation via nuclear factor-kappaB (NF-κB) signaling pathway in SE rats.

Phosphorylation of PRAS40 contributes to the activation of the PI3K/AKT/mTOR signaling pathway and the inhibition of autophagy following status epilepticus in rats.

Status epilepticus (SE) is a neurological disorder associated with high morbidity and mortality rates, and is often difficult to treat. Moreover, the underlying mechanism of SE remains unknown. The lithium-pilocarpine model is a validated animal model that can reproduce the main clinical and neuropathological features of SE. In the present study, this SE model was utilized and SE was successfully established in rats, as determined by the corresponding epileptic electroencephalogram. Histology, immunohistochemistry, western blot analysis and co-immunoprecipitation were used to detect the phosphorylation (p-) of AKT substrate of 40 kDa (PRAS40), the combination of p-PRAS40 and 14-3-3 protein and the activation of the PI3K/mTOR signaling pathway in SE. In addition, the present study analyzed the dynamics of the expression of autophagy-associated factors in the hippocampus after SE induction, and the influence of suppressing the p- of PRAS40 on the autophagy process was detected in the pathogenesis of SE. The results indicated that increased p-PRAS40 expression could activate the mTOR pathway to decrease the level of autophagy. However, inhibition of the mTOR signaling pathway promoted autophagy flux. These results may provide further understanding of p-PRAS40 functions in SE.

Expression and functional analysis of lncRNAs in the hippocampus of immature rats with status epilepticus

Long non‐coding RNAs (lncRNAs) have been implicated in the regulation of gene expression at various levels. However, to date, the expression profile of lncRNAs in status epilepticus (SE) was unclear. In our study, the expression profile of lncRNAs was investigated by high‐throughput sequencing based on a lithium/pilocarpine‐induced SE model in immature rats. Furthermore, weighted correlation network analysis (WGCNA), gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to construct co‐expression networks and establish functions of the identified hub lncRNAs in SE. The functional role of a hub lncRNA (NONRATT010788.2) in SE was investigated in an in vitro model. Our results indicated that 7082 lncRNAs (3522 up‐regulated and 3560 down‐regulated), which are involved in cell proliferation, inflammatory responses, angiogenesis and autophagy, were dysregulated in the hippocampus of immature rats with SE. Additionally, WGCNA identified 667 up‐regulated hub lncRNAs in turquoise module that were involved in apoptosis, inflammatory responses and angiogenesis via regulation of HIF‐1, p53 and chemokine signalling pathways and via inflammatory mediator regulation of TRP channels. Knockdown of an identified hub lncRNA (NONRATT010788.2) inhibited neuronal apoptosis in vitro. Taken together, our study is the first to demonstrate the expression profile and potential function of lncRNAs in the hippocampus of immature rats with SE. The defined hub lncRNAs may participate in the pathogenesis of SE via lncRNA‐miRNA‐mRNA network.

Inflammation: A Network in the Pathogenesis of Status Epilepticus.

Status epilepticus (SE) is an abnormally prolonged or recurrent epileptic seizure that is a serious, life-threatening medical emergency. Notably, it requires prompt and aggressive treatment. SE is characterized by high mortality and morbidity. However, its pathogenesis remains unclear. Numerous studies of SE have reported widespread brain inflammation, suggesting that inflammation plays a vital role in the occurrence and development of SE. This mini review article reviews the current knowledge with regard to the role of inflammation in SE.

Vitamin E inhibits activated chaperone-mediated autophagy in rats with status epilepticus

Seizures and status epilepticus induce an excessive production of reactive oxygen species leading to oxidative stress. Vitamin E, a classic antioxidant, has a neuroprotective effect on rats with seizures by regulating reactive oxygen species production. The activity of chaperone-mediated autophagy, a selective pathway for the degradation of cytosolic proteins in lysosomes, is enhanced during oxidative stress. Whether chaperone-mediated autophagy is induced during status epilepticus is not established. To address this problem, we used pilocarpine to elicit status epilepticus in rats. Lysosome-associated membrane protein 2a was used to estimate chaperone-mediated autophagy. We showed that compared to control animals, lysosome-associated membrane protein 2a at lysosomal membranes increased significantly in rats at 8 h, 16 h, and 24 h after induction of status epilepticus, which directly correlated with chaperone-mediated autophagy activity. Since reactive oxygen species are believed to be important in the pathogenesis of status epilepticus and are essential for the process of chaperone-mediated autophagy, we also sought to determine if pretreatment with vitamin E reduced chaperone-mediated autophagy. Pretreatment with vitamin E reduced oxidative stress and partially inhibited chaperone-mediated autophagy in brain at 24 h after status epilepticus versus vehicle. Taken together, these data show that chaperone-mediated autophagy is increased in rats with pilocarpine-induced status epilepticus through upregulation of de novo synthesis of lysosome-associated membrane protein 2a. Antioxidants such as vitamin E may partially inhibit activated chaperone-mediated autophagy.