期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 38, 期 5, 页码 857-868出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X17705786
关键词
Amitriptyline; lysophosphatidic acid; P-glycoprotein; blood-brain barrier; amyotrophic lateral sclerosis
资金
- Intramural Research Program at the National Institute of Environmental Health Sciences, National Institutes of Health
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.
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