English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

The blood–brain barrier is a microvascular network that (1) provides neuroprotection from metabolic and environmental toxins and (2) limits the delivery of therapeutics to the central nervous system (CNS). The ATP-binding cassette transporter P-glycoprotein contributes to the latter by actively pumping clinical substrates back into circulation before they can reach the brain parenchyma. Targeting P-glycoprotein has proven effective in increasing the delivery of therapeutics to their cerebral targets. We provide a novel mechanism to achieve this end in functioning, intact rat brain capillaries, whereby the bioactive phospholipid lysophosphatidic acid (LPA) and tricyclic antidepressant (TCA) amitriptyline reduce basal P-glycoprotein transport activity through a distinct lysophosphatidic acid 1 receptor-mediated signaling cascade that requires G-protein coupling, Src kinase, and ERK 1/2. Furthermore, we demonstrate the ability of LPA and TCA amitriptyline to decrease induced P-glycoprotein transport activity in a human SOD1 transgenic rat model of amyotrophic lateral sclerosis. This work may translate to new clinical strategies for increasing the cerebral penetration of therapeutics in patients suffering from CNS diseases marked by exacerbated pharmacoresistance.

Lysophosphatidic acid and amitriptyline signal through LPA1R to reduce P-glycoprotein transport at the blood–brain barrier