Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba. Facultad de Medicina. Avda de Menéndez Pidal s/n, 14004 Córdoba, Spain.
Biochem Pharmacol. 2010 Jun 15;79(12):1805-14. doi: 10.1016/j.bcp.2010.02.014. Epub 2010 Mar 3.
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.
脑微血管内皮细胞在维持脑血流、微血管张力和血脑屏障（BBB）功能方面发挥着积极作用。内源性 N-酰基多巴胺，如 N-花生四烯酰多巴胺（NADA）和 N-油酰多巴胺（OLDA），最近被确定为一类具有内源性大麻素和内香草素生物活性的新型脑神经递质。内源性大麻素是对致病刺激的反应而释放的，可能在神经保护中发挥重要作用。在这项研究中，我们证明了 NADA 可差异调节微血管脑内皮细胞系 b.end5 中 PGE2 和 PGD2 的释放。我们发现 NADA 激活了一种依赖于氧化还原的 p38 MAPK 途径，该途径稳定了 COX-2 mRNA，导致 COX-2 蛋白的积累，这取决于分子中的多巴胺部分，并且独立于 CB1 和 TRPV1 的激活。此外，NADA 抑制 mPGES-1 的表达和 PGE2 的释放，并上调 L-PGD 合酶的表达，从而增强 PGD2 的释放。因此，NADA 和其他同一家族的分子可能被包含在可以预防炎症条件下 BBB 损伤的脂质介质组中，我们的研究结果为 NADA 在中枢神经系统中的抗炎活性及其设计新的治疗策略来管理神经炎症性疾病的潜在机制提供了新的见解。
