Department of Pathology and Immunology, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland.
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Transl Psychiatry. 2017 Aug 15;7(8):e1206. doi: 10.1038/tp.2017.175.
Neuroinflammation and increased oxidative stress are believed to contribute to the development of psychiatric diseases. Animal studies have implicated NADPH oxidases (NOX) as relevant sources of reactive oxygen species in the brain. We have analyzed the expression of NOX isoforms in post-mortem brain samples from patients with psychiatric disorders (schizophrenia, bipolar disorder) and non-psychiatric subjects. Two collections from the Stanley Medical Research Institute were studied: the Array Collection (RNA, 35 individuals per group), and a neuropathology consortium collection (paraffin-embedded sections, 15 individuals per group). Quantitative PCR analysis revealed expression of NOX2 and NOX4 in prefrontal cortex. No impact of psychiatric disease on NOX4 levels was detected. Remarkably, the expression of NOX2 was specifically decreased in prefrontal and cingulate cortices of bipolar patients, as compared with controls and schizophrenic patients. NOX2 expression was not statistically associated with demographic parameters and post-mortem interval, but correlated with brain pH. Immunostaining demonstrated that NOX2 was predominantly expressed in microglia, which was corroborated by a decrease in the microglial markers CD68 and CD11b in the cingulate cortex of bipolar disorder patients. The analysis of potentially confounding parameters showed association of valproic acid prescription and heavy substance abuse with lower levels of NOX2. Taken together, we did not observe changes of NOX2 in schizophrenic patients, but a marked decrease of microglial markers and NOX2 in the brain of bipolar patients. This might be an underlying feature of bipolar disorder and/or a consequence of valproic acid treatment and substance abuse.
神经炎症和氧化应激增加被认为是导致精神疾病发展的原因。动物研究表明，NADPH 氧化酶（NOX）是大脑中活性氧的相关来源。我们分析了来自精神疾病（精神分裂症、双相情感障碍）和非精神疾病患者的死后大脑样本中 NOX 同工型的表达。研究了来自斯坦利医学研究所的两个集合：Array 集合（RNA，每组 35 人）和神经病理学联盟集合（石蜡包埋切片，每组 15 人）。定量 PCR 分析显示，NOX2 和 NOX4 在额皮质中表达。未检测到精神疾病对 NOX4 水平的影响。值得注意的是，与对照组和精神分裂症患者相比，双相情感障碍患者的额皮质和扣带回皮质中 NOX2 的表达特异性降低。NOX2 的表达与人口统计学参数和死后间隔没有统计学关联，但与脑 pH 值相关。免疫染色表明，NOX2 主要在小胶质细胞中表达，这得到了双相情感障碍患者扣带回皮质中小胶质细胞标志物 CD68 和 CD11b 减少的证实。对潜在混杂参数的分析表明，丙戊酸处方和大量滥用与 NOX2 水平降低有关。总之，我们没有观察到精神分裂症患者中 NOX2 的变化，但在双相情感障碍患者的大脑中观察到小胶质细胞标志物和 NOX2 的明显减少。这可能是双相情感障碍的潜在特征，也是丙戊酸治疗和物质滥用的后果。
