Journal
CURRENT PHARMACEUTICAL DESIGN
Volume 20, Issue 10, Pages 1463-1471Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/13816128113199990457
Keywords
Neuroprotection; Drug delivery; ABC transporters; Blood-brain barrier; P-gp; efflux pumps
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Funding
- National Institutes of Health, National Institute of Environmental Health Sciences
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At 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 TNF alpha/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.
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