核因子-κB：糖皮质激素诱导的亮氨酸拉链界面类似物可抑制阿尔茨海默病模型中的病理变化。
Nuclear factor-kappa B: Glucocorticoid-induced leucine zipper interface analogs suppress pathology in an Alzheimer's disease model.
作者信息
Srinivasan Mythily, Lahiri Niloy, Thyagarajan Anish, Witek Emily, Hickman Debra, Lahiri Debomoy K
机构信息
Department of Oral Pathology, Medicine and Radiology, Indiana University School of Dentistry, Indianapolis, IN, USA.
Provaidya LLC, Indiana University School of Dentistry, Indianapolis, IN, USA.
出版信息
Alzheimers Dement (N Y). 2018 May 24;4:488-498. doi: 10.1016/j.trci.2018.04.004. eCollection 2018.
INTRODUCTION
Glucocorticoid-induced leucine zipper is a regulatory protein that sequesters activated nuclear factor-kappa B p65. Previously, we showed that rationally designed analogs of the p65-binding domain of glucocorticoid-induced leucine zipper, referred to as glucocorticoid-induced leucine zipper analogs (GAs), inhibited amyloid β-induced metabolic activity and inflammatory cytokines in mixed brain cell cultures. Here, we investigate the therapeutic efficacy of GA in an Alzheimer's disease model.
METHODS
GA and control peptides were synthesized covalently as peptide amides with the cell-penetrating agent. C57Bl/6J mice induced with lipopolysaccharide-mediated neuroinflammation (250 mg/kg i.p/day for six days) were treated on alternate days with GA-1, GA-2, or control peptides (25 mg/kg i.v). Brain tissues were assessed for gliosis, cytokines, and antiapoptotic factors.
RESULTS
The brain tissues of GA-1- and GA-2-treated mice exhibited significantly reduced gliosis, suppressed inflammatory cytokines, and elevated antiapoptotic factors.
DISCUSSION
The antineuroinflammatory effects of GA suggest potential therapeutic application for Alzheimer's disease.
引言
糖皮质激素诱导亮氨酸拉链是一种调节蛋白，可隔离活化的核因子-κB p65。此前，我们发现，经合理设计的糖皮质激素诱导亮氨酸拉链p65结合域类似物（称为糖皮质激素诱导亮氨酸拉链类似物，即GAs）可抑制混合脑细胞培养物中β淀粉样蛋白诱导的代谢活性和炎性细胞因子。在此，我们研究GA在阿尔茨海默病模型中的治疗效果。
方法
GA和对照肽与细胞穿透剂共价合成为肽酰胺。对经脂多糖介导神经炎症诱导的C57Bl/6J小鼠（腹腔注射，250 mg/kg/天，共6天）隔天给予GA-1、GA-2或对照肽（静脉注射，25 mg/kg）。对脑组织进行胶质增生、细胞因子和抗凋亡因子评估。
结果
GA-1和GA-2处理小鼠的脑组织胶质增生显著减少，炎性细胞因子受到抑制，抗凋亡因子升高。
讨论
GA的抗神经炎症作用表明其在阿尔茨海默病治疗中具有潜在应用价值。
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