达格列净改善阿霉素诱导的大鼠化学脑和认知异常:调节AKT/GSK-3β和Wnt/β-Catenin通路

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Gehad Farouk Abdelhafez, Sylvia A. Boshra, Hagar B. Abo-Zalam, Sara M. Radwan
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引用次数: 0

摘要

在接受多柔比星(DOX)化疗的癌症幸存者中,由于氧化应激、神经炎症和DOX的凋亡作用,经常观察到认知障碍。Dapagliflozin (DAPA)因其强大的抗炎、抗氧化和抗凋亡特性而受到广泛关注。本研究旨在评估DAPA在减轻DOX引起的神经变性和认知功能障碍方面可能的神经保护特性。用DOX (2 mg/kg, ig)诱导化学脑,每周1次,连续4周。另外,连续28天给大鼠注射DAPA (2 mg/kg, p.o.)。认知行为测试表明,DAPA显著减轻了与DOX引起的认知障碍相关的行为缺陷。同样,DAPA逆转了组织病理学异常。机制上,DAPA通过降低NADPH氧化酶4 (NOX4)和丙二醛(MDA)的组织水平,提高超氧化物歧化酶(SOD)和谷胱甘肽(GSH)的活性来缓解DOX诱导的氧化应激。此外,DAPA通过减少脑组织中白细胞介素-1β (IL-1β)、肿瘤坏死因子α (TNF-α)和核因子κB (NF-κB)的产生,以及参与细胞凋亡的信号通路,包括蛋白激酶B (AKT)/糖原合成酶激酶3β (GSK-3β)通路和无翼相关整合位点(Wnt)/β-catenin通路,抑制神经炎症。DAPA抗凋亡作用的进一步证据是总caspase-3和NF-κB的p65亚基(NF-κB-p65)的免疫组织化学表达降低。DAPA通过提供抗氧化、抗炎和抗凋亡作用,对dox诱导的认知衰退具有神经保护作用。图形抽象
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dapagliflozin Ameliorates Doxorubicin-Induced Chemobrain and Cognitive Abnormalities in Rats: Modulation of AKT/GSK-3β and Wnt/β-Catenin Pathways

Cognitive impairments are frequently observed in cancer survivors who received chemotherapy based on doxorubicin (DOX), attributable to oxidative stress, neuroinflammation, and the apoptotic effect of DOX. Dapagliflozin (DAPA) has gained significant attention attributable to its powerful anti-inflammatory, antioxidant, and anti-apoptotic characteristics. The present investigation seeks to assess the possible neuroprotective properties of DAPA in alleviating neurodegeneration and cognitive dysfunction caused by DOX. Chemobrain was induced by DOX (2 mg/kg, i.p.) once weekly for four weeks. Additionally, rats were treated with DAPA (2 mg/kg, p.o.) for 28 consecutive days. DAPA markedly mitigated behavioral deficits associated with cognitive impairment induced by DOX, as demonstrated by cognitive behavioral tests. Likewise, DAPA reversed histopathological abnormalities. Mechanistically, DAPA alleviated the oxidative stress induced by DOX by reducing tissue levels of NADPH oxidase 4 (NOX4) and malondialdehyde (MDA) while enhancing the activities of superoxide dismutase (SOD) and glutathione (GSH). Additionally, DAPA suppressed neuroinflammation by attenuating the production of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa-B (NF-κB) in brain tissue, as well as the signaling pathways involved in apoptosis, including the Protein Kinase B (AKT)/Glycogen Synthase Kinase-3 beta (GSK-3β) pathway and the Wingless-related integration site (Wnt)/β-catenin pathway. Further evidence of DAPA’s anti-apoptotic effects was attributed to a decrease in the immunohistochemical expression of total caspase-3 and the p65 subunit of NF-κB (NF-κB-p65). DAPA induces neuroprotection against DOX-induced cognitive deterioration by providing antioxidant, anti-inflammatory, and anti-apoptotic effects.

Graphical Abstract

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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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