Targeting regulation of ABC efflux transporters in brain diseases: a novel therapeutic approach.
Blood-brain barrier efflux transporters limit the brain penetration and efficacy of various central nervous system drugs. In several CNS diseases, therapy- or pathophysiology-associated transcriptional activation of efflux transporters further strengthens the barrier function. Targeting the regulatory pathways that drive efflux transporter expression in different diseases represents an intriguing approach for prevention of these events thereby promoting delivery to the brain and enhancing or restoring drug efficacy. In particular, the approach holds the promise to preserve basal transporter expression and activity, which is of specific relevance in view of the protective function of efflux transport. The elucidation of the signaling cascades involved in transporter regulation is a major presupposition for the development of preventive strategies. Orphan nuclear receptors as well as the Wnt/beta-catenin signaling pathway have been implicated in drug-induced changes in transporter expression. Targeting these xenobiotic sensors is therefore discussed as a means to optimize brain delivery and therapeutic outcome. Relevant progress has also been made with the identification of key signaling events that drive P-glycoprotein expression in response to pathophysiological mechanisms. In the epileptic brain, complex signaling events involving cyclooxygenase-2 activity trigger P-glycoprotein expression in response to glutamate release and activation of endothelial NMDA receptors. Moreover, reactive oxygen species and inflammatory cytokines have been identified as regulatory factors which might affect P-glycoprotein in several CNS diseases. Recent data substantiated several interesting targets in the respective signaling cascades thereby rendering a basis for the ongoing development of innovative approaches to optimize central nervous system drug brain penetration and efficacy.
Potschka
Heidrun
H
Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstr. 16, D-80539 Munich, Germany. potschka@pharmtox.vetmed.uni-muenchen.de
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001927:Brain Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability; D002491:Central Nervous System Agents / Q000378:metabolism / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006801:Humans; D049990:Membrane Transport Modulators / Q000378:metabolism / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; D002491:Central Nervous System Agents; D049990:Membrane Transport Modulators