Department of Psychiatry, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly-Lausanne, Switzerland.
Antioxid Redox Signal. 2013 Apr 20;18(12):1428-43. doi: 10.1089/ars.2012.4858. Epub 2012 Oct 12.
Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due to an imbalance between pro-oxidants and antioxidant defense mechanisms has been proposed as a risk factor contributing to their pathophysiology.
Altered antioxidant systems and signs of increased oxidative stress are observed in peripheral tissues and brains of SZ and BD patients, including abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological, and neurochemical alterations analogous to pathologies observed in patients. Mice with GSH deficit display increased stress reactivity, altered social behavior, impaired prepulse inhibition, and exaggerated locomotor responses to psychostimulant injection. These behavioral changes are accompanied by N-methyl-D-aspartate receptor hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons, abnormal neuronal synchronization, altered dopamine neurotransmission, and deficient myelination.
Treatment with the GSH precursor and antioxidant N-acetylcysteine normalizes some of those deficits in mice, but also improves SZ and BD symptoms when given as adjunct to antipsychotic medication.
These data demonstrate the usefulness of GSH-deficient rodent models to identify the mechanisms by which a redox imbalance could contribute to the development of SZ and BD pathophysiologies, and to develop novel therapeutic approaches based on antioxidant and redox regulator compounds.
精神分裂症（SZ）和双相情感障碍（BD）被归类为两种不同的疾病。然而，越来越多的证据表明，这两种疾病在遗传、病理和流行病学方面具有共同特征。基于遗传和功能发现，由于促氧化剂和抗氧化防御机制之间的不平衡导致的氧化还原失调已被提出作为导致其病理生理学的危险因素。
在 SZ 和 BD 患者的外周组织和大脑中观察到抗氧化系统改变和氧化应激增加的迹象，包括谷胱甘肽 (GSH) 的异常前额叶水平，GSH 是主要的细胞氧化还原调节剂和抗氧化剂。在这里，我们回顾了来自啮齿动物模型的实验数据，这些数据表明，永久性和短暂性 GSH 缺乏会导致类似于患者中观察到的病理的行为、形态、电生理和神经化学改变。GSH 缺乏的小鼠表现出应激反应增加、社交行为改变、预脉冲抑制受损以及对精神兴奋剂注射的运动反应过度。这些行为变化伴随着 N-甲基-D-天冬氨酸受体功能低下、谷氨酸水平升高、钙调蛋白 GABA 中间神经元功能障碍、异常神经元同步、多巴胺神经传递改变和髓鞘形成缺陷。
用 GSH 前体和抗氧化剂 N-乙酰半胱氨酸治疗可使小鼠中的一些缺陷正常化，但当与抗精神病药物联合使用时，也可改善 SZ 和 BD 症状。
这些数据表明，GSH 缺乏的啮齿动物模型可用于确定氧化还原失衡如何导致 SZ 和 BD 病理生理学发展的机制，并开发基于抗氧化剂和氧化还原调节剂化合物的新治疗方法。
