Cipriano Mariateresa, Esposito Giueseppe, Negro Luana, Capoccia Elena, Sarnelli Giovanni, Scuderi Caterina, De Filippis Daniele, Steardo Luca, Iuvone Teresa
Department of Pharmacy, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy.
CNS Neurol Disord Drug Targets. 2015;14(7):828-37. doi: 10.2174/1871527314666150317224155.
Aβ-induced astrogliosis can worsen the eziopathogenesis of Alzheimer disease (AD) by the release of proinflammatory and pro-oxidant mediators. Activated glial cells may release also pro-angiogenic molecules. The role of angiogenesis in AD is still controversial: although angiogenesis brings oxygen and nutrients to injured tissue, it may also exacerbate reactive gliosis. Moreover, by altering blood-brain barrier permeability pro-angiogenic mediators promote passage of inflammatory/immune-competent cells into the brain, thereby exacerbating gliosis. The release of proangiogenic factors during astrogliosis may thus be a key-step in controlling AD progression. The endogenous fatty acid amide, palmitoylethanolamide (PEA), is a pleiotropic mediator exerting anti-inflammatory, antinociceptive and antiangiogenic effects in several in vitro and in vivo models of chronic-degenerative disease. In this study, we investigated the effects of PEA in AD angiogenesis and neuroinflammation by using conditioned medium from untreated and Aβ-treated C6 rat astroglioma cells and HUVEC human endothelial cells. PEA (10-10 M) concentration-dependently reduced expression of pro-inflammatory and pro-angiogenic markers in Aβ (1 μg/mL)-stimulated C6 cells. Moreover, culture medium from PEA-treated C6 cells reduced HUVEC cell proliferation as compared to cells treated with conditioned medium from Aβ-treated C6 cells. Immunocytochemical analysis revealed that PEA treatment inhibited nuclear levels of mitogen-activated protein kinase 1 (the main pro-angiogenic pathway) and cytoplasmic vascular endothelial growth factor in HUVEC cells receiving C6 conditioned medium. Finally, the peroxisome proliferator-activated receptor alpha inhibitor GW6471, added to Aβ-treated C6 cells blocked all PEA effects in this model, suggesting that PEA acts through a proliferator-activated receptor alpha-dependent mechanism on astroglial cells. Collectively, these data support the potential therapeutic utility of PEA in AD.
淀粉样β蛋白（Aβ）诱导的星形胶质细胞增生可通过释放促炎和促氧化介质，使阿尔茨海默病（AD）的发病机制恶化。活化的神经胶质细胞也可能释放促血管生成分子。血管生成在AD中的作用仍存在争议：虽然血管生成能为受损组织带来氧气和营养物质，但它也可能加剧反应性胶质细胞增生。此外，促血管生成介质通过改变血脑屏障通透性，促进炎症/免疫活性细胞进入大脑，从而加剧胶质细胞增生。因此，星形胶质细胞增生过程中促血管生成因子的释放可能是控制AD进展的关键步骤。内源性脂肪酸酰胺棕榈酰乙醇胺（PEA）是一种多效介质，在多种慢性退行性疾病的体外和体内模型中发挥抗炎、镇痛和抗血管生成作用。在本研究中，我们使用未处理和Aβ处理的C6大鼠星形胶质瘤细胞及人脐静脉内皮细胞（HUVEC）的条件培养基，研究了PEA对AD血管生成和神经炎症的影响。PEA（10⁻¹⁰ M）浓度依赖性地降低了Aβ（1 μg/mL）刺激的C6细胞中促炎和促血管生成标志物的表达。此外，与用Aβ处理的C6细胞的条件培养基处理的细胞相比，PEA处理的C6细胞的培养基降低了HUVEC细胞的增殖。免疫细胞化学分析显示，在接受C6条件培养基的HUVEC细胞中，PEA处理抑制了丝裂原活化蛋白激酶1（主要的促血管生成途径）的核水平和细胞质血管内皮生长因子。最后，添加到Aβ处理的C6细胞中的过氧化物酶体增殖物激活受体α抑制剂GW6471阻断了该模型中PEA的所有作用，表明PEA通过对星形胶质细胞的增殖物激活受体α依赖性机制发挥作用。总体而言，这些数据支持了PEA在AD中的潜在治疗效用。
