Greco Rosaria, Demartini Chiara, Zanaboni Anna Maria, Blandini Fabio, Amantea Diana, Tassorelli Cristina
Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, "C. Mondino" National Neurological Institute, Pavia, Italy.
Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, "C. Mondino" National Neurological Institute, Pavia, Italy; Department of Brain and Behavioural Sciences, University of Pavia, Italy.
Eur J Pharmacol. 2017 Apr 5;800:16-22. doi: 10.1016/j.ejphar.2017.02.008. Epub 2017 Feb 8.
The receptor for advanced glycation endproducts (RAGE) is a key mediator of neuroinflammation following cerebral ischemia. Nitric oxide (NO) plays a dualistic role in cerebral ischemia, depending on whether it originates from neuronal, inducible or endothelial synthase. Although a dynamic interplay between RAGE and NO pathways exists, its relevance in ischemic stroke has not been investigated. The aim of this study is to evaluate the effect of the NO synthase (NOS) inhibition on RAGE expression in rats subjected to transient middle cerebral artery occlusion (tMCAo). Full-length (fl-RAGE) gene expression was elevated in the striatum and, to a lesser extent, in the cortex of rats undergone tMCAo. The exacerbation of cortical damage caused by systemic administration of L-N-(1-iminoethyl)ornithine (L-NIO), a relatively selective inhibitor of endothelial NOS (eNOS), was associated with elevated mRNA levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α and fl-RAGE in both the cortex and the striatum. Conversely, NG-nitro-l-arginine methyl ester (L-NAME), a non-selective NOS inhibitor, decreased cortical damage, did not affect cerebral cytokine mRNA levels, while it increased fl-RAGE mRNA expression only in the striatum. Fl-RAGE striatal protein levels varied accordingly with observed mRNA changes in the striatum, while in the cortex, RAGE protein levels were reduced by tMCAo and further decreased following L-NIO treatment. Modulation of RAGE expression by different inhibitors of NOS may have opposite effects on transient cortical ischemia: the non selective inhibition of NOS activity is protective, while the selective inhibition of eNOS is harmful, probably via the activation of inflammatory pathways.
晚期糖基化终末产物受体（RAGE）是脑缺血后神经炎症的关键介质。一氧化氮（NO）在脑缺血中发挥双重作用，这取决于它是源自神经元型、诱导型还是内皮型一氧化氮合酶。尽管RAGE和NO信号通路之间存在动态相互作用，但其在缺血性卒中中的相关性尚未得到研究。本研究的目的是评估一氧化氮合酶（NOS）抑制对短暂性大脑中动脉闭塞（tMCAo）大鼠RAGE表达的影响。在接受tMCAo的大鼠纹状体中，全长（fl-RAGE）基因表达升高，在皮质中升高程度较小。全身给予相对选择性的内皮型NOS（eNOS）抑制剂L-N-（1-亚氨基乙基）鸟氨酸（L-NIO）导致皮质损伤加重，这与皮质和纹状体中白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α和fl-RAGE的mRNA水平升高有关。相反，非选择性NOS抑制剂NG-硝基-L-精氨酸甲酯（L-NAME）减少了皮质损伤，不影响脑细胞因子mRNA水平，而仅在纹状体中增加fl-RAGE mRNA表达。fl-RAGE纹状体蛋白水平与纹状体中观察到的mRNA变化一致，而在皮质中，RAGE蛋白水平在tMCAo后降低，L-NIO治疗后进一步降低。不同NOS抑制剂对RAGE表达的调节可能对短暂性皮质缺血产生相反的影响：非选择性抑制NOS活性具有保护作用，而选择性抑制eNOS则有害，可能是通过激活炎症途径。
