Abstract
BackgroundSystemic inflammation is a potent contributor to increased seizure susceptibility. However, information regarding the effects of systemic inflammation on cerebral vascular integrity that influence neuron excitability is scarce. Necroptosis is closely associated with inflammation in various neurological diseases. In this study, necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebrovascular components (e.g., endothelia cells).MethodsLipopolysaccharide (LPS) was used to induce systemic inflammation. Kainic acid intraperitoneal injection was used to measure the susceptibility of the mice to seizure. The pharmacological inhibitors C87 and GSK872 were used to block the signaling of TNFα receptors and necroptosis. In order to determine the features of the sepsis-associated response in the cerebral vasculature and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and for immunofluorescence staining to identify morphological changes in the endothelia and glia. In addition, microdialysis assay was used to assess the changes in extracellular potassium and glutamate levels in the brain.ResultsSome noteworthy findings, such as increased seizure susceptibility and brain endothelial necroptosis, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. C87 treatment, a TNFα receptor inhibitor, showed considerable attenuation of increased kainic acid-induced seizure susceptibility, endothelial cell necroptosis, microglia activation and restoration of Kir4.1 protein expression in LPS-treated mice. Treatment with GSK872, a RIP3 inhibitor, such as C87, showed similar effects on these changes following LPS injection.ConclusionsThe findings of this study showed that TNFα-mediated necroptosis induced cerebrovascular endothelial damage, neuroinflammation and astrocyte Kir4.1 dysregulation, which may coalesce to contribute to the increased seizure susceptibility in LPS-treated mice. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to the reduction of sepsis-associated brain endothelia cell injury, astrocyte ion channel dysfunction, and subsequent neuronal excitability.
Highlights
Seizure is a common acute complication of sepsis and systemic inflammation [1,2,3]
By employing an LPS-induced systemic inflammation mouse model, we found for role of tumor necrosis factor-α (TNFα)-mediated necroptosis in cerebrovascular endothelial cell damage and astrocytic Kir4.1 dysregulation, which possibly were related to an increase in the susceptibility to seizures in mice following systemic inflammation
The latency to initial seizure onset that was defined as seizure score stage 4 or more after kainic acid (KA) administration was significantly decreased in LPS-treated mice that were administered with 3 mg/kg KA, compared with that in LPS‐induced systemic inflammation induced the programmed necroptosis and Kir4.1 dysregulation in the hippocampus We determined the role of several signaling pathways that could be involved in the mechanisms of neuronal hyperexcitability following systemic inflammation, including pathways involved in apoptosis, necroptosis, and ion channel changes [28, 29]
Summary
Seizure is a common acute complication of sepsis and systemic inflammation [1,2,3]. It is induced by the hyperexcitability of circuits, caused by an imbalance between neuronal excitatory and inhibitory activities in the brain. Similar observations have been noted in postnatal and adult animals following systemic inflammation [3, 6, 8]. This evidence indicates that inflammatory processes initially from the peripheral circulation to the brain are a common and crucial mechanism in the pathophysiology of seizures and epilepsy. Necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebro‐ vascular components (e.g., endothelia cells)
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