Lixisenatide is a glucagon-like peptide-1 receptor (GLP-1 receptor) agonist that can be used for the treatment of type 2 diabetes[1]. Lixisenatide enhances insulin secretion in a glucose-dependent manner, inhibits glucagon release, and delays gastric emptying to reduce food intake, thereby exerting hypoglycemic and weight-loss-promoting effects[2]. Lixisenatide can also inhibit inflammatory responses by downregulating pro-inflammatory cytokines and blocking cellular signaling pathways[3]. Lixisenatide can slow the progression of motor disorders in early Parkinson's disease patients[4].
In vitro, pretreatment of human umbilical vein endothelial cells (HUVECs) with Lixisenatide (5-20nM) for 6 hours, followed by oxygen-glucose deprivation/reperfusion (OGD/R) to simulate ischemia-reperfusion injury, significantly improved cell viability, inhibited the accumulation of reactive oxygen species (ROS), and alleviated the impairment of endothelial cell tube formation ability induced by OGD/R. Lixisenatide also enhanced eNOS phosphorylation and nitric oxide (NO) production by activating the PI3K/Akt pathway[5]. Pretreatment of HEK-293 cells stably expressing GFP-labeled α-synuclein A53T (α-Syn-HEK-293 cells) and SH-SY5Y cells with Lixisenatide (10-20nM) for 6 hours, followed by stimulation with α-synuclein preformed fibrils (α-Syn PFFs, 3μg/mL) for 48 hours, significantly inhibited the phosphorylation (pS129) and aggregation of α-synuclein, reduced cell apoptosis and mitochondrial dysfunction, and improved cell viability[6].
In vivo, continuous treatment of high-fat diet-induced obese insulin-resistant mice with Lixisenatide (50nmol/kg; subcutaneous injection twice daily) for 40 days significantly improved insulin sensitivity in the mice, enhanced glucose tolerance and insulin secretion, and significantly improved the mice's novel object recognition memory ability[7]. Treatment of rats that had experienced transient ischemia-reperfusion injury with Lixisenatide (10μg/kg/day; subcutaneous injection) for 10 weeks improved left ventricular end-diastolic pressure and relaxation time and prevented pulmonary congestion[8].
References:
[1] Nauck MA, Quast DR, Wefers J, et al. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021 Apr;46:101102.
[2] Baker DE, Levien TL. Lixisenatide. Hosp Pharm. 2017 Jan;52(1):65-80.
[3] Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015 Dec 3;373(23):2247-57.
[4] Meissner WG, Remy P, Giordana C, et al. LIXIPARK Study Group. Trial of Lixisenatide in Early Parkinson's Disease. N Engl J Med. 2024 Apr 4;390(13):1176-1185.
[5] Xiao M, Lu D, Tian J, et al. The protective effects of GLP-1 receptor agonist lixisenatide on oxygen-glucose deprivation/reperfusion (OGD/R)-induced deregulation of endothelial tube formation. RSC Adv. 2020 Mar 10;10(17):10245-10253.
[6] Xu L, Chen G, Zhang L, et al. Lixisenatide ameliorated lipopolysaccharide (LPS)-induced expression of mucin and inflammation in bronchial epithelial cells. J Biochem Mol Toxicol. 2024 Jan;38(1):e23618.
[7] Lennox R, Flatt PR, Gault VA. Lixisenatide improves recognition memory and exerts neuroprotective actions in high-fat fed mice. Peptides. 2014 Nov;61:38-47.
[8] Wohlfart P, Linz W, Hübschle T, et al. Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies. J Transl Med. 2013 Mar 28;11:84. doi: 10.1186/1479-5876-11-84.
Lixisenatide是一种胰高血糖素样肽-1受体（GLP-1 receptor）激动剂，可用于治疗2型糖尿病[1]。Lixisenatide通过葡萄糖依赖的方式增强胰岛素分泌、抑制胰高血糖素释放，并能够延缓胃排空以减少食物摄入，从而发挥降血糖和促进体重减轻的作用[2]。Lixisenatide可通过下调促炎细胞因子和阻断细胞信号通路来抑制炎症反应[3]。Lixisenatide还能够减缓早期帕金森病患者的运动障碍进展[4]。
在体外，Lixisenatide（5-20nM）预处理人脐静脉内皮细胞（HUVECs）6小时，随后通过氧糖剥夺/再灌注（OGD/R）处理模拟缺血再灌注损伤，Lixisenatide显著改善细胞存活率，同时抑制活性氧（ROS）的积累，还缓解了OGD/R诱导的内皮细胞管形成能力受损，并通过激活PI3K/Akt通路增强eNOS磷酸化和一氧化氮（NO）的产生[5]。Lixisenatide（10-20nM）预处理稳定表达GFP标记α-突触核蛋白A53T的HEK-293细胞（α-Syn-HEK-293细胞）、SH-SY5Y细胞6小时，随后以α-突触核蛋白预制纤维（α-Syn PFFs，3μg/mL）刺激48小时，Lixisenatide显著抑制α-突触核蛋白的磷酸化（pS129）和聚集，同时减少细胞凋亡和线粒体功能障碍，并改善了细胞活力[6]。
在体内，Lixisenatide（50nmol/kg；每日两次皮下注射）持续40天处理高脂饮食诱导的肥胖胰岛素抵抗小鼠，Lixisenatide显著改善了小鼠的胰岛素敏感性，同时增强了葡萄糖耐量和胰岛素分泌，并显著改善了小鼠的新物体识别记忆能力[7]。Lixisenatide（10μg/kg/天；皮下注射）处理经历短暂缺血再灌注损伤的大鼠10周，Lixisenatide改善了左心室舒张末期压力和松弛时间，并预防了肺充血[8]。