Endogenous N-acyl-dopamines induce COX-2 expression in brain endothelial cells by stabilizing mRNA through a p38 dependent pathway.
Cerebral microvascular endothelial cells play an active role in maintaining cerebral blood flow, microvascular tone and blood brain barrier (BBB) functions. Endogenous N-acyl-dopamines like N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine (OLDA) have been recently identified as a new class of brain neurotransmitters sharing endocannabinoid and endovanilloid biological activities. Endocannabinoids are released in response to pathogenic insults and may play an important role in neuroprotection. In this study we demonstrate that NADA differentially regulates the release of PGE(2) and PGD(2) in the microvascular brain endothelial cell line, b.end5. We found that NADA activates a redox-sensitive p38 MAPK pathway that stabilizes COX-2 mRNA resulting in the accumulation of the COX-2 protein, which depends on the dopamine moiety of the molecule and that is independent of CB(1) and TRPV1 activation. In addition, NADA inhibits the expression of mPGES-1 and the release of PGE(2) and upregulates the expression of L-PGD synthase enhancing PGD(2) release. Hence, NADA and other molecules of the same family might be included in the group of lipid mediators that could prevent the BBB injury under inflammatory conditions and our findings provide new mechanistic insights into the anti-inflammatory activities of NADA in the central nervous system and its potential to design novel therapeutic strategies to manage neuroinflammatory diseases.
Navarrete
Carmen M
CM
Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba. Facultad de Medicina. Avda de Menéndez Pidal s/n, 14004 Córdoba, Spain. b72naruc@uco.es
Pérez
Moisés
M
de Vinuesa
Amaya García
AG
Collado
Juan A
JA
Fiebich
Bernd L
BL
Calzado
Marco A
MA
Muñoz
Eduardo
E
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004790:Enzyme Induction / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D001095:Arachidonic Acids; D012333:RNA, Messenger; C474941:arachidonyl dopamine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D004298:Dopamine