尽管粘菌素在治疗多重耐药革兰氏阴性菌菌株方面具有至关重要的抗菌活性；它表现出肾脏和神经元毒性，使其使用成为一个挑战。先前的研究调查了肠促胰岛素激素葡萄糖依赖性促胰岛素多肽（GIP）或胰高血糖素样肽-1（GLP-1）的神经保护和肾保护功效。本研究的重点是研究 Tirzepatide (Tirze)，一种 GLP-1/GIP 双重激动剂，作为粘菌素治疗方案中的辅助疗法，以减轻其肾脏和神经元并发症。大鼠分为：正常对照组、粘菌素治疗组接受粘菌素治疗（300,000 IU/kg/天，持续 7 天；腹膜内注射）。 Tirze 治疗组接受 Tirze（第 1、4、7 天 1.35 mg/kg；皮下注射）和每日粘菌素。 Tirze 有效增强了大鼠的组织病理学改变、肾功能参数和运动活动。 Tirze 通过调节在磷脂酰肌醇 3-激酶 (PI3K)/磷酸化蛋白激酶-B (p-Akt)/糖原合成酶激酶 (GSK)3-β 枢纽的损伤下进化的各种信号轴来发挥作用，从而减轻核因子 (NF) -κB (NF-κB) / 肿瘤坏死因子-α (TNF-α)、核因子红细胞 2 相关因子 2 (Nrf2)/ 谷胱甘肽 (GSH) 增加、ER 应激相关生物标志物下调（激活转录因子 4） (ATF4) 和 C/EBP 同源蛋白 (CHOP))，抗凋亡作用与神经胶质原纤维酸性蛋白 (GFAP) 免疫反应性的降低和磷酸化 c-AMP 反应元件结合 (p-CREB)/脑源性神经营养因子的增强相结合(BDNF)/酪氨酸激酶 B (TrkB) 神经保护途径。简而言之，Tirze 在粘菌素治疗方案中作为辅助治疗发挥着有前途的作用，除了能够抑制内质网应激相关生物标志物外，还具有抗炎、抗氧化和抗细胞凋亡作用，可预防粘菌素的肾毒性和神经毒性。版权所有 © 2024 Elsevier B.V.保留所有权利。

Although colistin has a crucial antibacterial activity in treating multidrug-resistant gram-negative bacteria strains; it exhibited renal and neuronal toxicities rendering its use a challenge. Previous studies investigated the incretin hormones either glucose-dependent insulinotropic polypeptide (GIP) or glucagonlike peptide-1 (GLP-1) for their neuroprotective and nephroprotective effectiveness. The present study focused on investigating Tirzepatide (Tirze), a dual GLP-1/GIP agonist, as an adjuvant therapy in the colistin treatment protocol for attenuating its renal and neuronal complications. Rats were divided into; The normal control group, the colistin-treated group received colistin (300,000 IU/kg/day for 7 days; i.p.). The Tirze-treated group received Tirze (1.35 mg/kg on the 1,4,7thdays; s.c.) and daily colistin. Tirze effectively enhanced histopathological alterations, renal function parameters, and locomotor activity in rats. Tirze mechanistically acted via modulating various signaling axes evolved under the insult of phosphatidylinositol 3-kinases (PI3K)/phosphorylated protein kinase-B (p-Akt)/ glycogen synthase kinase (GSK)3-β hub causing mitigation of nuclear factor (NF)-κB (NF-κB) / tumor necrosis factor-α (TNF-α), increment of nuclear factor erythroid 2-related factor 2 (Nrf2)/ glutathione (GSH), downregulation of ER stress-related biomarkers (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)), antiapoptotic effects coupling with reduction of glial fibrillary acidic protein (GFAP) immunoreactivity and enhancement of phosphorylated c-AMP response element-binding (p-CREB) / brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) neuroprotective pathway. Briefly, Tirze exerts a promising role as adjuvant therapy in the colistin treatment protocol for protection against colistin's nephro- and neurotoxicity according to its anti-inflammatory, antioxidant, and antiapoptotic impacts besides its ability to suppress ER stress-related biomarkers.Copyright © 2024 Elsevier B.V. All rights reserved.