Baroncelli Laura, Auel Stefanie, Rinne Lena, Schuster Ann-Kathrin, Brand Victoria, Kempkes Belinda, Dietrich Katharina, Müller Michael
Institut für Neuro- und Sinnesphysiologie, Universitätsmedizin Göttingen, Georg-August-Universität Göttingen, Humboldtallee 23, D-37073 Göttingen, Germany.
Institute of Neuroscience, National Research Council (CNR), via Giuseppe Moruzzi 1, I-56124 Pisa, Italy.
Antioxidants (Basel). 2022 Jul 20;11(7):1406. doi: 10.3390/antiox11071406.
Rett syndrome (RTT) is a severe neurodevelopmental disorder that typically arises from spontaneous germline mutations in the X-chromosomal methyl-CpG binding protein 2 () gene. For the first 6-18 months of life, the development of the mostly female patients appears normal. Subsequently, cognitive impairment, motor disturbances, hand stereotypies, epilepsy, and irregular breathing manifest, with previously learned skills being lost. Early mitochondrial impairment and a systemic oxidative burden are part of the complex pathogenesis, and contribute to disease progression. Accordingly, partial therapeutic merits of redox-stabilizing and antioxidant (AO) treatments were reported in RTT patients and -mutant mice. Pursuing these findings, we conducted a full preclinical trial on male and female mice to define the therapeutic value of an orally administered AO cocktail composed of vitamin E, N-acetylcysteine, and α-lipoic acid. AO treatment ameliorated some of the microcephaly-related aspects. Moreover, the reduced growth, lowered blood glucose levels, and the hippocampal synaptic plasticity of mice improved. However, the first-time detected intensified oxidative DNA damage in -mutant cortex persisted. The behavioral performance, breathing regularity, and life expectancy of -mutant mice did not improve upon AO treatment. Long-term-treated mice eventually became obese. In conclusion, the AO cocktail ameliorated a subset of symptoms of the complex RTT-related phenotype, thereby further confirming the potential merits of AO-based pharmacotherapies. Yet, it also became evident that long-term AO treatment may lose efficacy and even aggravate the metabolic disturbances in RTT. This emphasizes the importance of a constantly well-balanced redox balance for systemic well-being.
雷特综合征（RTT）是一种严重的神经发育障碍疾病，通常由X染色体甲基化CpG结合蛋白2（MECP2）基因的自发种系突变引起。在生命的最初6至18个月，大多数女性患者的发育看起来正常。随后，会出现认知障碍、运动障碍、手部刻板动作、癫痫和呼吸不规则等症状，之前所学的技能也会丧失。早期线粒体损伤和全身性氧化负担是复杂发病机制的一部分，并促成疾病进展。因此，在RTT患者和Mecp2突变小鼠中报道了氧化还原稳定和抗氧化（AO）治疗的部分治疗效果。基于这些发现，我们对雄性和雌性小鼠进行了全面的临床前试验，以确定由维生素E、N-乙酰半胱氨酸和α-硫辛酸组成的口服AO鸡尾酒的治疗价值。AO治疗改善了一些与小头畸形相关的方面。此外，Mecp2突变小鼠生长减缓、血糖水平降低以及海马突触可塑性得到改善。然而，首次在Mecp2突变皮质中检测到的氧化DNA损伤加剧仍然存在。AO治疗后，Mecp2突变小鼠的行为表现、呼吸规律性和预期寿命并未改善。长期接受治疗的Mecp2突变小鼠最终变得肥胖。总之，AO鸡尾酒改善了复杂的RTT相关表型的一部分症状，从而进一步证实了基于AO的药物治疗的潜在价值。然而，同样明显的是，长期AO治疗可能会失去疗效，甚至加重RTT中的代谢紊乱。这强调了维持系统健康所需的氧化还原平衡持续良好平衡的重要性。
