Status Epilepticus Induces Vasogenic Edema via Tumor Necrosis Factor-α/ Endothelin-1-Mediated Two Different Pathways

Abstract

Status epilepticus (SE) induces vasogenic edema in the piriform cortex with disruptions of the blood-brain barrier (BBB). However, the mechanisms of vasogenic edema formation following SE are still unknown. Here we investigated the endothelin B (ETB) receptor-mediated pathway of SE-induced vasogenic edema. Following SE, the release of tumor necrosis factor-α (TNF-α) stimulated endothelin-1 (ET-1) release and expression in neurons and endothelial cells. In addition, TNF-α-induced ET-1 increased BBB permeability via ETB receptor-mediated endothelial nitric oxide synthase (eNOS) activation in endothelial cells. ETB receptor activation also increased intracellular reactive oxygen species by NADPH oxidase production in astrocytes. These findings suggest that SE results in BBB dysfunctions via endothelial-astroglial interactions through the TNF-α-ET-1-eNOS/NADPH oxidase pathway, and that these ETB receptor-mediated interactions may be an effective therapeutic strategy for vasogenic edema in various neurological diseases.

Endothelial NOS activation induces the blood–brain barrier disruption via ER stress following status epilepticus

“…5). Consistent with our previous study (Kim et al, 2013), Cav-1 peptide did not affect eNOS expression in endothelial cells following SE (data not shown). Furthermore, the volume of vasogenic edema was 4.8 mm 3 in the PC of vehicle-pretreated animals at 3 days after SE.…”

“…Leakage of serum-derived components into the brain parenchyma results in neuronal hyperexcitability and seizure onset ( Therefore, dysfunction of the BBB leads to epileptogenesis and contributes to progression of epilepsy (Nitsch et al, 1985;Cornford and Oldendorf, 1986;Deli et al, 2005;Sztriha et al, 1986;Seiffert et al, 2004). Recently, we have reported that SE triggers a signaling cascade leading to NO production derived from eNOS in endothelial cells (Kim et al, 2013). Since the increased NO synthesis affects BBB permeability in various pathophysiological conditions (Sharma et al, 2000;Wu and Tsirka, 2009) we suggested that eNOS may involve BBB disruption following SE (Kim et al, 2013).…”

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

“…There are many reports in the literature showing that SE can cause brain edema that can by itself, contribute to the epileptogenic process [63][64][65], although the mechanisms underlying this process are unknown. Edema resulting from seizures in human or experimental model can be of two types, cytotoxic edema and vasogenic edema [63][64][65][66][67][68][69].…”

“…Edema resulting from seizures in human or experimental model can be of two types, cytotoxic edema and vasogenic edema [63][64][65][66][67][68][69]. In the cytotoxic edema, the glutamate hyperstimulation causes intracellular Ca 2+ increase and promotes cytotoxicity in neurons and glial cells [64,70].…”

“…Conversely, in the vasogenic edema, the cellular signaling triggered by SE can induce proinflammatory cytokines release and increases the production of kinins [71][72][73][74][75][76][77][78]. The kinins along with the cytokines may affect the junction of blood vessel epithelial cells and reduce the integrity of the tight junctions in endothelial cells walls, leading to a dysfunction of the blood brain barrier and consequently increasing the vascular permeability and accumulation of extracellular fluid [63,70,79,80]. There are a number of studies showing robust evidence that IL-1β released following seizures may be pro-convulsant in experimental models of epilepsy [6,14,15,76,81].…”