Pal Akansha, Goel Falguni, Sharma Anushka, Garg Vipin Kumar
Department of Pharmaceutical Technology, Meerut Institute of Engineering & Technology (MIET), Meerut, India.
Mol Divers. 2025 Jun 30. doi: 10.1007/s11030-025-11274-8.
Autism spectrum disorder is a multifaceted neurodevelopmental disorder that involves impaired social interaction, communication challenges, and repetitive behavior. The developing evidence emphasizes a key pathophysiological role for oxidative stress in ASD, which is initiated by an imbalance between ROS generation and antioxidant defense mechanisms. Increased levels of lipid peroxidation, protein oxidation, and DNA damage have been repeatedly found in ASD patients, indicating generalized oxidative damage and mitochondrial impairment. Redox homeostasis disruption is responsible for synaptic dysfunction, neuroinflammation, and disrupted neuronal signaling, worsening the fundamental symptoms of ASD. In this regard, antioxidant therapeutics have attracted a great deal of attention as putative modulators of oxidative stress and neuroinflammation in ASD. Promising candidates such as N-acetylcysteine, glutathione precursors, coenzyme Q10, vitamin E, and polyphenols have been found to be potentially effective against oxidative damage and enhancing behavioral outcomes. The therapeutic potency of such compounds is directly related to their structure-activity relationships, which control their antioxidant activity, bioavailability, and blood-brain barrier permeability. SAR studies have revealed key functional groups, such as thiols, phenolic hydroxyls, and quinone moieties, which increase the free radical scavenging activity and neuroprotective properties of these compounds. In spite of promising preclinical and clinical outcomes, the best dosing, treatment duration, and combinatorial strategies for antioxidant treatments in ASD are poorly characterized. In this review, the biochemical basis of oxidative stress in ASD is examined, the mechanistic understanding of antioxidant-based interventions is assessed, and the structure-activity relationships that dictate their therapeutic value are discussed. Clarifying these molecular complexities will facilitate the development of more potent and targeted antioxidant therapies, bringing new hope for controlling ASD-related oxidative pathologies.
自闭症谱系障碍是一种多方面的神经发育障碍，涉及社交互动受损、沟通障碍和重复行为。越来越多的证据强调氧化应激在自闭症谱系障碍中起关键的病理生理作用，这是由活性氧生成与抗氧化防御机制之间的失衡引发的。在自闭症谱系障碍患者中反复发现脂质过氧化、蛋白质氧化和DNA损伤水平升高，表明存在全身性氧化损伤和线粒体功能障碍。氧化还原稳态破坏导致突触功能障碍、神经炎症和神经元信号传导紊乱，使自闭症谱系障碍的基本症状恶化。在这方面，抗氧化疗法作为自闭症谱系障碍中氧化应激和神经炎症的假定调节剂引起了广泛关注。已发现诸如N-乙酰半胱氨酸、谷胱甘肽前体、辅酶Q10、维生素E和多酚等有前景的候选物对氧化损伤具有潜在疗效并能改善行为结果。这些化合物的治疗效力与其构效关系直接相关，构效关系控制着它们的抗氧化活性、生物利用度和血脑屏障通透性。构效关系研究揭示了关键官能团，如硫醇、酚羟基和醌部分，这些官能团增加了这些化合物的自由基清除活性和神经保护特性。尽管临床前和临床结果很有前景，但自闭症谱系障碍抗氧化治疗的最佳剂量、治疗持续时间和联合策略仍未明确。在本综述中，研究了自闭症谱系障碍中氧化应激的生化基础，评估了基于抗氧化剂干预的机制理解，并讨论了决定其治疗价值的构效关系。阐明这些分子复杂性将有助于开发更有效和有针对性的抗氧化疗法，为控制自闭症谱系障碍相关的氧化病理带来新希望。
