Misra Sakshi, Rajput Prabha, Kaur Amandeep
Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, GT Road, Moga, 142001, Punjab, India.
Department of Pharmacology, School of Pharmacy & Technology Management, SVKM's NMIMS University, Shirpur Campus, Shirpur, India.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jan 28. doi: 10.1007/s00210-025-03827-3.
In examining the enduring consequences of diabetes, recent research has focused on the anticipated outcomes of the condition. Specifically, cognitive impairment has been linked to diabetes mellitus dating back to the discovery of insulin. This study delves into the neuroprotective effects of TZP, i.e. tirzepatide a dual GIP and GLP-1 receptor agonist that works by mimicking these two gut hormones, against cognitive impairment associated with type 2 diabetes mellitus (T2DM). T2DM-like zebrafish model of varying age groups was created through a 6-week administration of a high-fat diet (HFD). Parameters such as body weight, body mass index, and blood glucose levels were monitored, and behavioural assessments (T-maze, novel tank diving test, and inhibitory avoidance test) were conducted at the conclusion of the protocol to assess learning and memory. Additionally, lipid profile biochemical parameters (MDA, AChEs, and GSH), molecular markers (IL-1β, IL-10, TNF-α, Bcl-2, Bax, GSK-3β, and AMPK), and histopathological examinations were performed. Treatment with the novel GLP-1 and GIP dual agonist TZP (10 nM/kg, i.p.) significantly ameliorated cognitive impairment, as evidenced by behavioural parameters, and restored antioxidant like GSH (p < 0.05) and catalase (p < 0.05) and anti-inflammatory marker levels, i.e. IL-10 (p < 0.05) compared to the HFD group. TZP also mitigated abnormal glucose (73.2 ± 5.889) and lipid profiles (TG 0.159 ± 0.0075 and TC 0.100 ± 0.0020) in hyperglycaemic zebrafish. This study suggests that the positive effects of TZP on cognition and memory may stem from its neuroprotective capabilities, potentially attributed to its antioxidant, anti-inflammatory, and anti-apoptotic properties, as well as its ability to enhance AMPK levels as GLP-1 agonist has the potential to increase the level of AMPK.
在研究糖尿病的长期后果时，近期研究聚焦于该病症的预期结果。具体而言，认知障碍与糖尿病的关联可追溯到胰岛素的发现。本研究深入探究了TZP（即替尔泊肽，一种双重GIP和GLP - 1受体激动剂，通过模拟这两种肠道激素发挥作用）对2型糖尿病（T2DM）相关认知障碍的神经保护作用。通过为期6周的高脂饮食（HFD）喂养建立了不同年龄组的T2DM样斑马鱼模型。监测体重、体重指数和血糖水平等参数，并在实验方案结束时进行行为评估（T迷宫、新水箱潜水试验和抑制性回避试验）以评估学习和记忆能力。此外，还进行了脂质谱生化参数（丙二醛、乙酰胆碱酯酶和谷胱甘肽）、分子标志物（白细胞介素 - 1β、白细胞介素 - 10、肿瘤坏死因子 - α、Bcl - 2、Bax、糖原合成酶激酶 - 3β和AMPK）以及组织病理学检查。新型GLP - 1和GIP双重激动剂TZP（10 nM/kg，腹腔注射）治疗显著改善了认知障碍，行为参数证明了这一点，并且与HFD组相比，恢复了抗氧化剂如谷胱甘肽（p < 0.05）和过氧化氢酶（p < 0.05）以及抗炎标志物白细胞介素 - 10（p < 0.05）的水平。TZP还减轻了高血糖斑马鱼的异常血糖（73.2 ± 5.889）和脂质谱（甘油三酯0.159 ± 0.0075和总胆固醇0.100 ± 0.0020）。本研究表明，TZP对认知和记忆的积极作用可能源于其神经保护能力，这可能归因于其抗氧化、抗炎和抗凋亡特性，以及其作为GLP - 1激动剂提高AMPK水平的能力，因为GLP - 1激动剂有潜力增加AMPK的水平。
