Elshafey Mohamed, Mostafa Hany K K, El-Agawy Mosaab Salah El-Din, Safwat Marwa Mohamed, El-Sherbiny Mohamed, Ebrahim Hasnaa Ali, El Hasnaoui-Saadani Raja, Elsherbiny Nehal M, Abomosallam Mohamed, Ibrahim Ateya M, Ali Ehab Kamal, Ali Zeinab A, Elsherbini Dalia Mahmoud Abdelmonem
Physiological Sciences Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia; Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Physiological Sciences Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia.
Tissue Cell. 2025 Oct 14;98:103184. doi: 10.1016/j.tice.2025.103184.
Aging is an important risk factor for neurodegenerative disease and requires the development of safe and widely accessible strategies to mitigate brain aging. Atorvastatin, primarily recognized for its cholesterol-lowering properties, has largely unexplored potential in modulating autophagy and safeguarding against age-related cognitive decline. The current study aimed to explore the potential beneficial impact of atorvastatin on structural and functional brain alterations in aged rats by analyzing its influence on autophagy and related processes, including apoptosis, inflammation, and oxidative stress. The study involved twenty-four rats, which were separated into three distinct groups: the adult control group (3-4 months old), the untreated aged group (20-24 months old) that received saline orally, and the aged treated group (20-24 months old) that received atorvastatin orally for 30 days at a dose of 20 mg/kg. Memory performance was evaluated using behavioural assessments. The cortical levels of oxidative stress markers, namely Nrf-2, MDA, GSH, and SOD, along with inflammatory mediators such as TNF-α and IL-1β, were quantified. Histopathological changes and immune staining of NF-κB, Nrf-2, TNF-α, Anti-SQSTM1/p62, LC3, and CD68 were evaluated. Furthermore, the levels of p62, caspase-3, and SIRT1 expression were determined. Atorvastatin enhanced memory function in aged rats. This was achieved by restoring the oxidative-antioxidant balance in the cortex, as evidenced by increased levels of Nrf-2, GSH, and SOD, along with a reduction in MDA levels. TNF-α, IL-6, and NF-κB cortical expression was suppressed, indicating their anti-inflammatory effects. Furthermore, autophagy was enhanced, as shown by elevated LC3 and decreased p62 expression, whereas apoptosis was mitigated through the downregulation of Caspase-3. Histological analysis corroborated the preservation of cortical structure and protection against neurodegenerative changes associated with aging. In conclusion, atorvastatin showed neuroprotective impact in this aged rat model by reducing oxidative stress, inflammation, and apoptosis, while modulating autophagy markers. These preclinical findings warrant further investigation, including clinical studies, to evaluate their therapeutic potential in humans.
衰老为神经退行性疾病的一个重要风险因素，需要制定安全且广泛适用的策略来减轻大脑衰老。阿托伐他汀主要因其降胆固醇特性而为人所知，在调节自噬以及预防与年龄相关的认知衰退方面，其潜力在很大程度上尚未得到探索。本研究旨在通过分析阿托伐他汀对自噬及相关过程（包括细胞凋亡、炎症和氧化应激）的影响，探讨其对老年大鼠大脑结构和功能改变的潜在有益作用。该研究涉及24只大鼠，分为三个不同的组：成年对照组（3 - 4个月大）、口服生理盐水的未治疗老年组（20 - 24个月大），以及以20毫克/千克的剂量口服阿托伐他汀30天的老年治疗组（20 - 24个月大）。使用行为评估来评价记忆表现。对氧化应激标志物（即Nrf - 2、丙二醛、谷胱甘肽和超氧化物歧化酶）的皮质水平，以及诸如肿瘤坏死因子 - α和白细胞介素 - 1β等炎症介质进行了定量分析。评估了组织病理学变化以及NF - κB、Nrf - 2、肿瘤坏死因子 - α、抗SQSTM1/p62、微管相关蛋白1轻链3（LC3）和CD68的免疫染色情况。此外，还测定了p62、半胱天冬酶 - 3和沉默信息调节因子1（SIRT1）的表达水平。阿托伐他汀增强了老年大鼠的记忆功能。这是通过恢复皮质中的氧化 - 抗氧化平衡实现的，表现为Nrf - 2、谷胱甘肽和超氧化物歧化酶水平升高，同时丙二醛水平降低。肿瘤坏死因子 - α、白细胞介素 - 6和NF - κB的皮质表达受到抑制，表明其具有抗炎作用。此外，自噬增强，表现为LC3升高和p62表达降低，而细胞凋亡通过半胱天冬酶 - 3的下调得到缓解。组织学分析证实了皮质结构的保留以及对与衰老相关的神经退行性变化的保护作用。总之，阿托伐他汀通过降低氧化应激、炎症和细胞凋亡，同时调节自噬标志物，在该老年大鼠模型中显示出神经保护作用。这些临床前研究结果值得进一步研究，包括临床研究，以评估其在人类中的治疗潜力。
