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RL-118 通过抑制 11β-HSD1 促进自噬,与减轻氧化应激和炎症相关,可增强 SAMP8 小鼠模型的认知表现。

11β-HSD1 Inhibition by RL-118 Promotes Autophagy and Correlates with Reduced Oxidative Stress and Inflammation, Enhancing Cognitive Performance in SAMP8 Mouse Model.

机构信息

Secció de Farmacologia i Toxicologia and Institut de Neurociències, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), and Institute of Biomedicine (IBUB), Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain.

出版信息

Mol Neurobiol. 2018 Dec;55(12):8904-8915. doi: 10.1007/s12035-018-1026-8. Epub 2018 Apr 2.

DOI:10.1007/s12035-018-1026-8
PMID:29611102
Abstract

Elevated glucocorticoid (GC) exposure is widely accepted as a key factor in the age-related cognitive decline in rodents and humans. 11β-HSD1 is a key enzyme in the GCs pathway, catalyzing the conversion of 11β-dehydrocorticosterone to corticosterone in mice, with possible implications in neurodegenerative processes and cognitive impairment. Here, we determined the effect of a new 11β-HSD1 inhibitor, RL-118, administered to 12-month-old senescence-accelerated mouse-prone 8 (SAMP8) mice with neuropathological AD-like hallmarks and widely used as a rodent model of cognitive dysfunction. Behavioral tests (open field and object location) and neurodegeneration molecular markers were studied. After RL-118 treatment, increased locomotor activity and cognitive performance were found. Likewise, we found changes in hippocampal autophagy markers such as Beclin1, LC3B, AMPKα, and mTOR, indicating a progression in the autophagy process. In line with autophagy increase, a diminution in phosphorylated tau species (Ser 396 and Ser 404) jointly with an increase in ADAM10 and sAPPα indicated that an improvement in removing the abnormal proteins by autophagy might be implicated in the neuroprotective role of the 11β-HSD1 inhibitor. In addition, gene expression of oxidative stress (OS) and inflammatory markers, such as Hmox1, Aldh2, Il-1β, and Ccl3, were reduced in old treated mice in comparison to that of the control group. Consistent with this, we further demonstrate a significant correlation with autophagy markers and cognitive improvement and significant inverse correlation with autophagy, OS, and neuroinflammation markers. We concluded that inhibition of 11β-HSD1 by RL-118 prevented neurodegenerative processes and cognitive decline, acting on autophagy process, being an additional neuroprotective mechanism not described previously.

摘要

糖皮质激素(GC)水平升高被广泛认为是啮齿动物和人类与年龄相关的认知能力下降的关键因素。11β-羟类固醇脱氢酶 1(11β-HSD1)是 GC 途径中的关键酶,在小鼠中催化 11β-脱氢皮质酮转化为皮质酮,可能与神经退行性过程和认知障碍有关。在这里,我们确定了一种新型 11β-HSD1 抑制剂 RL-118 对具有神经病理学 AD 样特征的衰老加速小鼠 prone 8(SAMP8)小鼠的影响,SAMP8 被广泛用作认知功能障碍的啮齿动物模型。研究了行为测试(旷场和物体定位)和神经退行性分子标志物。在 RL-118 治疗后,发现运动活性和认知表现增加。同样,我们发现海马自噬标志物如 Beclin1、LC3B、AMPKα 和 mTOR 的变化,表明自噬过程的进展。与自噬增加一致,磷酸化 tau 种(Ser 396 和 Ser 404)减少,同时 ADAM10 和 sAPPα 增加,表明通过自噬清除异常蛋白的能力提高可能与 11β-HSD1 抑制剂的神经保护作用有关。此外,与对照组相比,老年治疗小鼠的氧化应激(OS)和炎症标志物(如 Hmox1、Aldh2、Il-1β 和 Ccl3)的基因表达减少。与此一致,我们进一步证明与自噬标志物和认知改善呈显著相关性,与自噬、OS 和神经炎症标志物呈显著负相关。我们得出结论,RL-118 通过抑制 11β-HSD1 来预防神经退行性过程和认知能力下降,作用于自噬过程,是以前未描述的另一种神经保护机制。

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