Carota Giuseppe, Distefano Alfio, Spampinato Mariarita, Giallongo Cesarina, Broggi Giuseppe, Longhitano Lucia, Palumbo Giuseppe A, Parenti Rosalba, Caltabiano Rosario, Giallongo Sebastiano, Di Rosa Michelino, Polosa Riccardo, Bramanti Vincenzo, Vicario Nunzio, Li Volti Giovanni, Tibullo Daniele
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.
Department of Scienze Mediche Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia", University of Catania, 95123 Catania, Italy.
Antioxidants (Basel). 2022 Aug 18;11(8):1596. doi: 10.3390/antiox11081596.
Hemoglobin and iron overload is considered the major contributor to intracerebral hemorrhage (ICH)-induced brain injury. Accumulation of iron in the brain leads to microglia activation, inflammation and cell loss. Current available treatments for iron overload-mediated disorders are characterized by severe adverse effects, making such conditions an unmet clinical need. We assessed the potential of α-lipoic acid (ALA) as an iron chelator, antioxidant and anti-inflammatory agent in both in vitro and in vivo models of iron overload. ALA was found to revert iron-overload-induced toxicity in HMC3 microglia cell line, preventing cell apoptosis, reactive oxygen species generation and reducing glutathione depletion. Furthermore, ALA regulated gene expression of iron-related markers and inflammatory cytokines, such as IL-6, IL-1β and TNF. Iron toxicity also affects mitochondria fitness and biogenesis, impairments which were prevented by ALA pre-treatment in vitro. Immunocytochemistry assay showed that, although iron treatment caused inflammatory activation of microglia, ALA treatment resulted in increased ARG1 expression, suggesting it promoted an anti-inflammatory phenotype. We also assessed the effects of ALA in an in vivo zebrafish model of iron overload, showing that ALA treatment was able to reduce iron accumulation in the brain and reduced iron-mediated oxidative stress and inflammation. Our data support ALA as a novel approach for iron-overload-induced brain damage.
血红蛋白和铁过载被认为是脑出血（ICH）所致脑损伤的主要促成因素。脑内铁的蓄积会导致小胶质细胞活化、炎症和细胞丢失。目前针对铁过载介导疾病的现有治疗方法存在严重不良反应，使得这类疾病成为尚未满足的临床需求。我们在铁过载的体外和体内模型中评估了α-硫辛酸（ALA）作为铁螯合剂、抗氧化剂和抗炎剂的潜力。研究发现，ALA可逆转铁过载诱导的HMC3小胶质细胞系毒性，防止细胞凋亡、活性氧生成并减少谷胱甘肽耗竭。此外，ALA调节铁相关标志物和炎性细胞因子（如IL-6、IL-1β和TNF）的基因表达。铁毒性还会影响线粒体健康和生物发生，而体外预先用ALA处理可预防这些损伤。免疫细胞化学分析表明，尽管铁处理会导致小胶质细胞炎性活化，但ALA处理会使精氨酸酶1（ARG1）表达增加，表明其促进了抗炎表型。我们还评估了ALA在铁过载的体内斑马鱼模型中的作用，结果表明ALA处理能够减少脑内铁蓄积，并减轻铁介导的氧化应激和炎症。我们的数据支持将ALA作为一种治疗铁过载所致脑损伤的新方法。
