Signaling Pathways that Regulate Basal ABC Transporter Activity at the Blood- Brain Barrier
David S. Miller and Ronald E. CannonAffiliation:
Laboratory of Toxicology and Pharmacology National Institute of Environmental Health, Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
AbstractAt the blood-brain barrier, ATP-binding cassette (ABC) transporters, such as, P-glycoprotein (MDR1, ABCB1) and breast cancer related protein (BCRP, ABCG2) limit CNS uptake of foreign chemicals. Thus, they are neuroprotective, but they also distinguish poorly between neurotoxicants and therapeutic drugs. So they are major obstacles to CNS pharmacotherapy. The present review is focused on new findings in animal models in vitro and in vivo showing that basal transport activity of P-glycoprotein and Bcrp can be rapidly and transiently reduced through targeting of specific signaling pathways within the brain capillary endothelium. Three pathways have been identified: estrogen signaling to Bcrp, vascular endothelial growth factor signaling to P-glycoprotein and TNFα/PKC/ sphingolipid signaling to P-glycoprotein. Translation of these results to the clinic could provide improved pharmacotherapy for a number of CNS diseases, including, brain cancer, neuroAIDS and epilepsy.
Neuroprotection, Drug delivery, ABC transporters, Blood-brain barrier, P-gp, efflux pumps.
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