Loi Manuela, Valenti Francesca, Medici Giorgio, Mottolese Nicola, Candini Giulia, Bove Angelica Marina, Trebbi Federica, Pincigher Luca, Fato Romana, Bergamini Christian, Trazzi Stefania, Ciani Elisabetta
Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy.
Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 42, 40126 Bologna, Italy.
Int J Mol Sci. 2025 Feb 28;26(5):2204. doi: 10.3390/ijms26052204.
deficiency disorder (CDD), a developmental encephalopathy caused by mutations in the cyclin-dependent kinase-like 5 () gene, is characterized by a complex and severe clinical picture, including early-onset epilepsy and cognitive, motor, visual, and gastrointestinal disturbances. This disease still lacks a medical treatment to mitigate, or reverse, its course and improve the patient's quality of life. Although CDD is primarily a genetic brain disorder, some evidence indicates systemic abnormalities, such as the presence of a redox imbalance in the plasma and skin fibroblasts from CDD patients and in the cardiac myocytes of a mouse model of CDD. In order to shed light on the role of oxidative stress in the CDD pathophysiology, in this study, we aimed to investigate the therapeutic potential of Coenzyme Q10 (CoQ10), which is known to be a powerful antioxidant, using in vitro and in vivo models of CDD. We found that CoQ10 supplementation not only reduces levels of reactive oxygen species (ROS) and normalizes glutathione balance but also restores the levels of markers of DNA damage (γ-H2AX) and senescence (lamin B1), restoring cellular proliferation and improving cellular survival in a human neuronal model of CDD. Importantly, oral supplementation with CoQ10 exerts a protective role toward lipid peroxidation and DNA damage in the heart of a murine model of CDD, the (+/-) female mouse. Our results highlight the therapeutic potential of the antioxidant supplement CoQ10 in counteracting the detrimental oxidative stress induced by CDKL5 deficiency.
细胞周期蛋白依赖性激酶样5（CDKL5）缺乏症（CDD）是一种由CDKL5基因突变引起的发育性脑病，其临床症状复杂且严重，包括早发性癫痫以及认知、运动、视觉和胃肠道功能障碍。这种疾病仍然缺乏能够减轻或逆转其病程并改善患者生活质量的治疗方法。尽管CDD主要是一种遗传性脑部疾病，但一些证据表明存在全身异常，例如CDD患者的血浆和皮肤成纤维细胞以及CDD小鼠模型的心肌细胞中存在氧化还原失衡。为了阐明氧化应激在CDD病理生理学中的作用，在本研究中，我们旨在使用CDD的体外和体内模型研究辅酶Q10（CoQ10）的治疗潜力，CoQ10是一种已知的强大抗氧化剂。我们发现补充CoQ10不仅可以降低活性氧（ROS）水平并使谷胱甘肽平衡正常化，还可以恢复DNA损伤（γ-H2AX）和衰老（核纤层蛋白B1）标志物的水平，在CDD的人类神经元模型中恢复细胞增殖并提高细胞存活率。重要的是，口服CoQ10对CDD小鼠模型（CDKL5(+/-)雌性小鼠）的心脏脂质过氧化和DNA损伤具有保护作用。我们的结果突出了抗氧化剂补充剂CoQ10在对抗CDKL5缺乏引起的有害氧化应激方面的治疗潜力。
