Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP-4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson’s Disease Mouse Models

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ritu Soni, Vaishali Pankaj, Sudeep Roy, Amit Khairnar and Jigna Shah*, 
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引用次数: 0

Abstract

Parkinson’s disease (PD) is one of the most common progressive neurodegenerative pathologies that leads to dopaminergic deficiency and motor manifestations. Alpha-synuclein aggregation is a characteristic hallmark of PD pathogenesis. These aggregates facilitate the formation of Lewy bodies and degeneration. The epidemiological evidence demonstrates a definitive association of diabetes with PD risk. Considering this, many antidiabetic agents such as GLP-1 agonists and DPP-4 inhibitors are being explored as alternative PD therapeutics. This study evaluated the neuroprotective effect of the DPP-4 inhibitor sitagliptin mediated by the PI3K/AKT and Nrf2 pathways in PD models. In silico studies were conducted to determine the binding affinity, stability, and ADMET properties of DPP-4 inhibitors with target proteins. Sitagliptin (15 mg/kg p.o.) was administered in rotenone (30 mg/kg p.o. for 28 days)-induced and MPTP/P (25 mg/kg i.p. MPTP and 100 mg/kg probenecid i.p. twice a week for 5 weeks)-induced PD mouse (C57/BL6) models. Neurobehavioral assessments were carried out throughout the study. Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β, GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological studies, and immunohistochemistry were carried out at the end of the study. The in silico studies demonstrate better binding, stability, and ADMET profile of sitagliptin with both target proteins. Sitagliptin restored cognitive and motor deficits in both rotenone- and MPTP/P-induced mouse models. There was upregulation of PI3K, AKT, Nrf2, CREB, and BDNF levels and downregulation of GSK-3β, NF-κB, and alpha-synuclein levels in both models after treatment with sitagliptin. However, GLP1 levels were not significantly restored, indicating a GLP1-independent mechanism. It also restored histopathological alterations and TH+ neuronal loss induced by rotenone and MPTP/P. These findings demonstrate that sitagliptin exhibits neuroprotective action mediated by upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and MPTP/P mouse models of PD.

Abstract Image

DPP-4抑制剂西格列汀上调PI3K/AKT和Nrf2通路对化学诱导帕金森病小鼠模型的神经保护作用
帕金森病(PD)是一种最常见的进行性神经退行性疾病,可导致多巴胺能缺乏和运动表现。α -突触核蛋白聚集是帕金森病发病机制的特征标志。这些聚集体促进路易体的形成和变性。流行病学证据表明糖尿病与PD风险有明确的关联。考虑到这一点,许多抗糖尿病药物,如GLP-1激动剂和DPP-4抑制剂正在被探索作为PD治疗的替代药物。本研究评估了PI3K/AKT和Nrf2通路介导的DPP-4抑制剂西格列汀在PD模型中的神经保护作用。通过计算机研究确定DPP-4抑制剂与靶蛋白的结合亲和力、稳定性和ADMET特性。西格列汀(15 mg/kg每日一次)用于鱼藤酮(30 mg/kg每日一次,28 d)诱导和MPTP/P (25 mg/kg每日一次,MPTP和100 mg/kg每日一次,每周2次,连续5周)诱导的PD小鼠(C57/BL6)模型。在整个研究过程中进行了神经行为评估。研究结束时进行生化(GSH、MDA)、分子检测(AKT、Nrf2、PI3K、GSK-3β、GLP1、CREB、BDNF、NF-κB、α -突触核蛋白)、组织病理学和免疫组织化学检测。硅研究表明西格列汀与两种靶蛋白的结合、稳定性和ADMET谱更好。西格列汀恢复鱼藤酮和MPTP/ p诱导小鼠模型的认知和运动缺陷。西格列汀治疗后,两种模型的PI3K、AKT、Nrf2、CREB、BDNF水平均上调,GSK-3β、NF-κB、α -突触核蛋白水平均下调。然而,GLP1水平没有明显恢复,表明GLP1不依赖于机制。它还能恢复鱼藤酮和MPTP/P诱导的组织病理学改变和TH+神经元的丢失。这些发现表明西格列汀在鱼藤酮和MPTP/P小鼠PD模型中具有通过上调PI3K/AKT和Nrf2通路介导的神经保护作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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