Behrens M Margarita, Sejnowski Terrence J
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Neuropharmacology. 2009 Sep;57(3):193-200. doi: 10.1016/j.neuropharm.2009.06.002. Epub 2009 Jun 11.
An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a pro-oxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PV-interneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, although essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redox balance leading to schizophrenia symptoms in late adolescence and early adulthood.
大脑氧化还原状态的失衡可能是精神分裂症潜在病理生理学的一部分。炎症介质，如白细胞介素-6（IL-6），可使氧化还原平衡向促氧化状态倾斜，在精神分裂症患者中一直发现其水平发生改变。然而，疾病中氧化还原状态改变与观察到的大脑功能改变之间的关系尚不清楚。精神分裂症药理学模型的最新数据表明，氧化还原和炎症失衡可能通过快速放电中间神经元的改变与该疾病的病理生理学直接相关。成年期反复暴露于NMDA受体拮抗剂氯胺酮会增加大脑中促炎细胞因子白细胞介素-6的水平，通过激活产生超氧化物的酶NADPH氧化酶（Nox2），导致小清蛋白中间神经元（PV-中间神经元）的GABA能表型丧失，并导致前额叶皮质抑制活性降低。单次暴露于氯胺酮后未观察到这种效应，这表明首次暴露于NMDA受体拮抗剂会使大脑致敏，从而在反复暴露时对PV-中间神经元产生有害影响。IL-6/Nox2途径激活对PV-中间神经元系统的影响在成年大脑中是可逆的，但在发育中的皮质中是永久性的。PV-中间神经元的缓慢发育虽然对出生后大脑发育期间神经元回路的形成至关重要，但增加了它们对可永久影响其成熟过程的有害损伤的易感性。因此，在具有遗传易感性的个体中，IL-6/Nox2途径的持续激活可能是一个环境因素，它会打破氧化还原平衡，导致青春期晚期和成年早期出现精神分裂症症状。
