胰高血糖素样肽-1(GLP-1)受体激动剂与神经炎症:对神经退行性疾病治疗的启示。

Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment.

机构信息

Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States.

Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

出版信息

Pharmacol Res. 2022 Dec;186:106550. doi: 10.1016/j.phrs.2022.106550. Epub 2022 Nov 11.

Abstract

Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation.

摘要

慢性、过度的神经炎症是阿尔茨海默病 (AD) 和帕金森病 (PD) 等神经退行性疾病的一个关键特征。然而,在这些疾病的临床治疗中,神经炎症途径尚未得到有效靶向。有趣的是,炎症增加和神经退行性疾病风险与 2 型糖尿病 (T2DM) 和胰岛素抵抗 (IR) 有关,这表明减轻 T2DM 病理的治疗方法可能同样成功地治疗神经炎症和神经退行性病理。胰高血糖素样肽-1 (GLP-1) 是一种肠促胰岛素激素,可促进健康的胰岛素信号传递、调节血糖水平和抑制食欲。因此,许多 GLP-1 受体 (GLP-1R) 刺激药物已被美国食品和药物管理局 (FDA) 和相关全球监管机构开发和批准用于治疗 T2DM。此外,GLP-1R 刺激药物在神经退行性疾病的临床前模型中与抗炎、神经营养和神经保护特性相关,因此有望被重新用于治疗神经退行性疾病。在这篇综述中,我们讨论了肠促胰岛素信号、神经炎症途径以及神经炎症、大脑 IR 和神经退行性疾病之间的交集,重点是 AD 和 PD。我们还概述了目前 FDA 批准的肠促胰岛素受体刺激药物和正在开发的药物,包括单分子、双分子和三分子受体激动剂,并强调了那些正在进行临床试验用于治疗神经退行性疾病的药物。我们提出,将已经批准的 GLP-1R 激动剂重新用于治疗神经退行性疾病,可能是通过抑制神经炎症来改善 AD 和 PD 病理的一种安全、有效且具有成本效益的策略。

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