罗氟司特对脂多糖诱导小鼠脑组织神经炎性改变的保护作用。

IF 1.8 4区 医学 Q3 CLINICAL NEUROLOGY Current Alzheimer research Pub Date : 2023-01-01 DOI:10.2174/1567205020666230503141817
Nisha Kumari, Shivam Kumar Pandey, Mohammed Zunaid Akhtar, Mangaldeep Dey, Avtar Singh Gautam, Anjuman Nanda, Aman Tiwari, Rakesh Kumar Singh
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引用次数: 0

摘要

背景:小胶质细胞过度激活促进脑组织中各种第二信使和炎症标志物的产生,导致神经炎症和神经变性,从而可能导致认知能力下降。环核苷酸是参与神经发生、突触可塑性和认知调节的重要第二信使之一。这些环核苷酸的水平是由磷酸二酯酶的异构体,特别是PDE4B在大脑中维持的。PDE4B水平和环核苷酸之间的不平衡可能导致神经炎症加重。方法:以500 μg/kg的剂量,隔天腹腔注射脂多糖(LPS),连续7 d引起全身炎症反应。这可能导致神经胶质细胞的激活,并可能激活脑组织中的氧化应激和神经炎症标志物。此外,在该模型中口服罗氟司特(0.1、0.2和0.4 mg/kg)可改善这些动物的氧化应激标志物、神经炎症和神经行为参数。结果:LPS对小鼠脑组织氧化应激、乙酰胆碱酯酶水平升高、过氧化氢酶水平降低及记忆损伤有不良影响。此外,它还增强了PDE4B酶的活性和表达,导致环核苷酸水平下降。此外,罗氟司特治疗可改善认知能力下降,降低乙酰胆碱酯酶水平,提高过氧化氢酶水平。罗氟司特也以剂量依赖的方式降低PDE4B的表达,LPS上调PDE4B的表达。结论:罗氟米司特具有抗神经炎作用,可逆转lps诱导的小鼠认知能力下降。
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Roflumilast Protects against Neuroinflammatory Alterations in Brain Tissues of Lipopolysaccharide-induced Mice Model.

Background: Microglial overactivation promotes the production of various second messengers and inflammatory markers in brain tissue, resulting in neuroinflammation and neurodegeneration, which may lead to cognitive decline. The cyclic nucleotides are one of the important second messengers involved in the regulation of neurogenesis, synaptic plasticity, and cognition. The levels of these cyclic nucleotides are maintained by phosphodiesterase enzyme isoforms, particularly PDE4B, in the brain. An imbalance between PDE4B levels and cyclic nucleotides may lead to aggravating neuroinflammation.

Methods: Lipopolysaccharides (LPS) were administered intraperitoneally on alternate days for 7 days at a dose of 500 μg/kg in mice, which triggered systemic inflammation. This may lead to the activation of glial cells and may activate oxidative stress and neuroinflammatory markers in brain tissue. Furthermore, oral administration of roflumilast (0.1, 0.2, and 0.4 mg/kg) in this model ameliorated oxidative stress markers, neuroinflammation and improved neurobehavioral parameters in these animals.

Results: The detrimental effect of LPS increased oxidative stress, AChE enzyme levels, and decreased catalase levels in brain tissues, along with memory impairment in animals. Moreover, it also enhanced the activity and expression of the PDE4B enzyme, resulting in a decline in cyclic nucleotide levels. Furthermore, treatment with roflumilast improved the cognitive decline, decreased AChE enzyme level, and increased the catalase enzyme level. Roflumilast also reduced the PDE4B expression in a dose-dependent manner, which LPS up-regulated.

Conclusion: Roflumilast has shown an anti-neuroinflammatory effect and reversed the cognitive decline in LPS-induced mice model.

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来源期刊
Current Alzheimer research
Current Alzheimer research 医学-神经科学
CiteScore
4.00
自引率
4.80%
发文量
64
审稿时长
4-8 weeks
期刊介绍: Current Alzheimer Research publishes peer-reviewed frontier review, research, drug clinical trial studies and letter articles on all areas of Alzheimer’s disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer’s disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer’s disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer''s disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer’s disease. Current Alzheimer Research provides a comprehensive ''bird''s-eye view'' of the current state of Alzheimer''s research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.
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