. These subtypes include TNF receptor I or p55 receptor, and TNF receptor II or p75 receptor . Recently, we reported that an impairment of endothelial cell function via TNF- mediated p65Thr 485 NFB phosphorylation is involved in SE-induced vasogenic edema, which result in extensive neutrophil 9 Endothelin-1 in Seizure-Induced Vasogenic 21363929 Edema doi: 10.1371/journal.pone.0074458.g005 infiltration and neuron-astroglial loss via TNFp75R. In the present study, the basal level of TNF- concentration was 106.1 pg/ml in the PC, although TNF- expression was undetectable in normal brains. This TNF- induction may be due to surgical injury during the insertion of the guide cannula for the microdialysis probe. However, SE significantly induced TNF- synthesis and released it into brain parenchyma, and the TNF- concentration was 151.8 pg/ml. Furthermore, sTNFp55R and SN50 pretreatment attenuated SE-induced vasogenic edema via the preservation of SMI-71. These findings indicate that the TNF-/NFB-mediated neuroinflammatory responses in the brain parenchyma play a crucial role in BBB disruptions following SE. However, sTNFp55R pretreatment did not completely reduce the volume of SE-induced vasogenic edema. Although TNF- has been shown to directly increases BBB permeability in various experimental disease models, these findings indicate that TNF- itself may not be the only upstream modifier of vasogenic edema development. ET-1 is one of the potent and long-lasting vasoconstrictors that work in a paracrine and autocrine fashion. ET-1 binds to the ETA receptor that expresses in smooth muscle cells within the cerebral vasculature. Therefore, several lines of evidence indicate that ET-1 is an important mediator of cortical brain damage in terms of its potent vasoconstriction MedChemExpress PTK/ZK action inducing the decline of cerebral blood flow. Thus, targeting ET-1 biosynthesis may be a strategy for preventing neurovascular injury. Although ET-1 is expressed in brain parenchyma, ET-1 cannot cross or alter the permeability of the BBB. Therefore, it is likely that the neurovascular action of ET-1 as a vasoconstrictor would be limited during vasogenic edema formation. However, ET-1 also acts 2578618 as vasodilator when it binds to the ETB receptor. The ETB receptor is predominantly expressed in neurons, glial cells, and capillary endothelial cells. ETB receptor activation in endothelial cells results in vasodilation via NO production, which causes rapid and shortlived vasodilation. In the present study, we 
found upregulated ET-1 expression in endothelial cells prior to SE- 10 Endothelin-1 in Seizure-Induced Vasogenic Edema doi: 10.1371/journal.pone.0074458.g006 11 Endothelin-1 in Seizure-Induced Vasogenic Edema doi: 10.1371/journal.pone.0074458.g007 induced vasogenic edema formation via the TNF-/NFBmediated pathway. Furthermore, ET-1 stimulated eNOS to synthesize NO in endothelial cells through the ETB receptor. In turn, NO-dependent reactive nitrogen species-mediated reduction in SMI-71 expression resulted in BBB disruption, leading to vasogenic edema. Therefore, our findings indicate that TNF–induced ET-1 expression in endothelial cells may be a potential factor to increase BBB permeability via ETB receptor-mediated eNOS activation following SE. In the present study, reductions in dystrophin/AQP4 expression correlated with the up-regulation of ETB receptor in astrocytes after SE. These reductions were accompanied by an increase in 4-HNE levels in astrocytes. Interestingly, Dong et al. rep
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