Fig. 7.

Inflammatory and oxidative stress signaling. (A) NFkB, a primary transcription factor, is activated by infectious and inflammatory stimuli. NF-κB binds to the promoters of its target genes and stimulates transcription. Both ABCB1 and ABCG2 are regulated via NFkB signaling at the blood-brain barrier. (B) Upon activation, Wnt binds to the Frizzled receptor, which recruits axin and inhibits GSK3Β. Consequently, the destruction complex cannot assemble, and β-catenin accumulates in the cytosol. After translocation into the nucleus, β-catenin acts as transcription factor and induces transcription of both ABCB1 and ABCG2. (C) In isolated brain capillaries, TNFα signals through TNF receptor 1 activating the endothelin converting enzyme, which, in turn, leads to the production of endothelin 1, which signals through the endothelin receptor B to activate the inducible nitric oxide synthase. NO stimulates protein kinase C, which leads to the activation of NF-κB, which upregulates ABCB1 protein expression and transport activity. (D) Seizure-induced glutamate release activates NMDAR- cytosolic phospholipase A2-COX-2 signaling that leads to the generation of prostaglandin E2 (PGE2) by the microsomal prostaglandin synthase. PGE2 activates the prostaglandin EP1 receptor, which via NF-κB activation ultimately leads to increased ABC transporter expression and activity levels at the blood-brain barrier. Created with BioRender.com.