Mukem Sirirak, Sayoh Ibrahim, Maungchanburi Saowanee, Thongbuakaew Tipsuda
School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand.
Department of Anatomy, Faculty of Science and Technology, Princess of Naradhiwas University, Narathiwat 96000, Thailand.
Adv Pharmacol Pharm Sci. 2023 Sep 12;2023:6641347. doi: 10.1155/2023/6641347. eCollection 2023.
Increasing evidence highlights that excessive iron accumulation in the brain plays a vital role in neuronal senescence and is implicated in the pathogenesis of age-related neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Therefore, the chemical compounds that eliminate an iron overload may provide better protection against oxidative stress conditions that cause the accumulation of senescent cells during brain aging. Ebselen has been identified as a strongly useful compound in the research on redox biology mechanisms. We hypothesized that ebselen could alleviate an iron overload-induced oxidative stress and consequently reverses the senescence-like phenotypes in the neuronal cells. In the present study, SH-SY5Y cells were treated with ferric ammonium citrate (FAC) before ebselen, and the evaluation of the cellular iron homeostasis, the indicators of oxidative stress, and the onset of senescence phenotypes and mechanisms were carried out accordingly. Our findings showed that ebselen ameliorated the FAC-mediated iron overload by decreasing the expression of divalent metal transporter 1 (DMT1) and ferritin light chain (FT-L) proteins. In contrast, it increased the expression of ferroportin 1 (FPN1) protein and its correlation led to a decrease in the expression of the cytosolic labile iron pool (LIP). Furthermore, ebselen significantly reduced reactive oxygen species (ROS) and rescued the mitochondrial membrane potential (ΔΨm). Notably, ebselen restored the biomarkers of cellular senescence by reducing the number of senescence-associated -galactosidase (SA--gal) positive cells and senescence-associated secretory phenotypes (SASP). This also suppressed the expression of p53 protein targeting DNA damage response (DDR)/p21 cyclin-dependent kinase (CDK) inhibitor through a mTORC1 signaling pathway. Potentially, ebselen could be a therapeutic agent for treating brain aging and AD by mitigating iron accumulation and restoring senescence in SH-SY5Y cells.
越来越多的证据表明，大脑中过量的铁积累在神经元衰老中起着至关重要的作用，并与包括阿尔茨海默病（AD）和帕金森病（PD）在内的年龄相关性神经退行性疾病的发病机制有关。因此，能够消除铁过载的化合物可能会更好地抵御氧化应激条件，而这种氧化应激条件会在大脑衰老过程中导致衰老细胞的积累。依布硒仑已被确定为氧化还原生物学机制研究中一种非常有用的化合物。我们假设依布硒仑可以减轻铁过载诱导的氧化应激，从而逆转神经元细胞中的衰老样表型。在本研究中，在使用依布硒仑之前先用柠檬酸铁铵（FAC）处理SH-SY5Y细胞，并据此对细胞铁稳态、氧化应激指标以及衰老表型和机制的发生进行评估。我们的研究结果表明，依布硒仑通过降低二价金属转运蛋白1（DMT1）和铁蛋白轻链（FT-L）蛋白的表达来改善FAC介导的铁过载。相反，它增加了铁转运蛋白1（FPN1）蛋白的表达，其相关性导致胞质不稳定铁池（LIP）的表达降低。此外，依布硒仑显著降低了活性氧（ROS）并恢复了线粒体膜电位（ΔΨm）。值得注意的是，依布硒仑通过减少衰老相关β-半乳糖苷酶（SA-β-gal）阳性细胞的数量和衰老相关分泌表型（SASP）来恢复细胞衰老的生物标志物。这也通过mTORC1信号通路抑制了靶向DNA损伤反应（DDR）/p21细胞周期蛋白依赖性激酶（CDK）抑制剂的p53蛋白的表达。依布硒仑有可能通过减轻SH-SY5Y细胞中的铁积累和恢复衰老来成为治疗大脑衰老和AD的治疗剂。
