Abdelhafez Gehad Farouk, Boshra Sylvia A, Abo-Zalam Hagar B, Radwan Sara M
Biochemistry Department, Faculty of Pharmacy, October 6 University, Giza, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, October 6 University, Giza, Egypt.
Neurochem Res. 2025 Sep 5;50(5):286. doi: 10.1007/s11064-025-04538-0.
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.
在接受基于阿霉素（DOX）的化疗的癌症幸存者中，经常观察到认知障碍，这归因于氧化应激、神经炎症以及DOX的凋亡作用。达格列净（DAPA）因其强大的抗炎、抗氧化和抗凋亡特性而备受关注。本研究旨在评估DAPA在减轻DOX引起的神经退行性变和认知功能障碍方面可能具有的神经保护特性。通过每周一次腹腔注射DOX（2mg/kg），持续四周来诱导化疗脑。此外，大鼠连续28天口服DAPA（2mg/kg）。认知行为测试表明，DAPA显著减轻了与DOX诱导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。从机制上讲，DAPA通过降低组织中烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX4）和丙二醛（MDA）的水平，同时增强超氧化物歧化酶（SOD）和谷胱甘肽（GSH）的活性，减轻了DOX诱导的氧化应激。此外，DAPA通过减弱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，以及包括蛋白激酶B（AKT）/糖原合酶激酶-3β（GSK-3β）途径和无翅相关整合位点（Wnt）/β-连环蛋白途径在内的凋亡相关信号通路，抑制了神经炎症。DAPA抗凋亡作用的进一步证据归因于总半胱天冬酶-3和NF-κB的p65亚基（NF-κB-p65）免疫组化表达的降低。DAPA通过提供抗氧化、抗炎和抗凋亡作用，诱导对DOX诱导的认知衰退的神经保护作用。
