In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 9 ( 2022-9-9), p. e0268590-
Kurzfassung:
Chronic inflammation and blood–brain barrier dysfunction are key pathological hallmarks of neurological disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Major drivers of these pathologies include pro-inflammatory stimuli such as prostaglandins, which are produced in the central nervous system by the oxidation of arachidonic acid in a reaction catalyzed by the cyclooxygenases COX1 and COX2. Monoacylglycerol lipase hydrolyzes the endocannabinoid signaling lipid 2-arachidonyl glycerol, enhancing local pools of arachidonic acid in the brain and leading to cyclooxygenase-mediated prostaglandin production and neuroinflammation. Monoacylglycerol lipase inhibitors were recently shown to act as effective anti-inflammatory modulators, increasing 2-arachidonyl glycerol levels while reducing levels of arachidonic acid and prostaglandins, including PGE 2 and PGD 2 . In this study, we characterized a novel, highly selective, potent and reversible monoacylglycerol lipase inhibitor (MAGLi 432) in a mouse model of lipopolysaccharide-induced blood–brain barrier permeability and in both human and mouse cells of the neurovascular unit: brain microvascular endothelial cells, pericytes and astrocytes. We confirmed the expression of monoacylglycerol lipase in specific neurovascular unit cells in vitro , with pericytes showing the highest expression level and activity. However, MAGLi 432 did not ameliorate lipopolysaccharide-induced blood–brain barrier permeability in vivo or reduce the production of pro-inflammatory cytokines in the brain. Our data confirm monoacylglycerol lipase expression in mouse and human cells of the neurovascular unit and provide the basis for further cell-specific analysis of MAGLi 432 in the context of blood–brain barrier dysfunction caused by inflammatory insults.
Materialart:
Online-Ressource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0268590
DOI:
10.1371/journal.pone.0268590.g001
DOI:
10.1371/journal.pone.0268590.g002
DOI:
10.1371/journal.pone.0268590.g003
DOI:
10.1371/journal.pone.0268590.g004
DOI:
10.1371/journal.pone.0268590.g005
DOI:
10.1371/journal.pone.0268590.g006
DOI:
10.1371/journal.pone.0268590.s001
DOI:
10.1371/journal.pone.0268590.s002
DOI:
10.1371/journal.pone.0268590.s003
DOI:
10.1371/journal.pone.0268590.s004
DOI:
10.1371/journal.pone.0268590.s005
DOI:
10.1371/journal.pone.0268590.s006
DOI:
10.1371/journal.pone.0268590.s007
DOI:
10.1371/journal.pone.0268590.s008
DOI:
10.1371/journal.pone.0268590.s009
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2022
ZDB Id:
2267670-3
Permalink