Regulation of ABC Transporters at the Blood-Brain Barrier: New Targets for CNS Therapy

Targeting BBB ABC transporters in epilepsy and brain cancer. (A) Seizure-induced glutamate release up-regulates P-glycoprotein via a signaling pathway that involves the NMDA receptor (NMDAR), arachidonic acid (AA), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), the prostanoid E1 receptor (EP1), and the transcription factor NF-κB (nuclear factor-κB). E2 (17β-estradiol) signals reduction of BCRP expression (B) and its functional activity through a nongenomic signaling pathway that involves ERα/β, (C) the phosphatase and tensin homolog (PTEN, a tumor suppressor), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase 3 (GSK3), transporter internalization, and proteasomal degradation.