Itokawa Masanari, Miyashita Mitsuhiro, Arai Makoto, Miyata Toshio
*Project for Schizophrenia and Affective Disorders Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
†United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan.
Biochem Soc Trans. 2014 Apr;42(2):468-72. doi: 10.1042/BST20140044.
We have identified idiopathic carbonyl stress in a subpopulation of schizophrenic patients. We first identified a patient with a mutation in GLO1 (glyoxalase I) who showed increased AGE (advanced glycation end-product) levels and decreased vitamin B6 levels. By applying the observations from this rare case to the general schizophrenic population, we were able to identify a subset of patients (20%) for whom carbonyl stress may represent a causative pathophysiological process. Genetic defects in GLO1 increase the risk of carbonyl stress 5-fold, and the resulting increased AGE levels correlate significantly with PANSS (Positive and Negative Syndrome Scale) scored negative symptoms. Pyridoxamine, an active form of vitamin B6 and scavenger for carbonyl stress, could represent a novel and efficacious therapeutic agent for these treatment-resistant symptoms. In the present article, we describe a unique research approach to identify the causative process in the pathophysiology of a subset of schizophrenia. Our findings could form the basis of a schizophrenia subtype classification within this very heterogeneous disease and ultimately lead to better targeted therapy.
我们在一部分精神分裂症患者中发现了特发性羰基应激。我们首先发现了一名患有GLO1（乙二醛酶I）突变的患者，该患者的晚期糖基化终产物（AGE）水平升高，维生素B6水平降低。通过将这一罕见病例的观察结果应用于一般精神分裂症患者群体，我们能够识别出一部分患者（20%），羰基应激可能是他们致病的病理生理过程。GLO1的基因缺陷使羰基应激风险增加5倍，由此导致的AGE水平升高与阳性和阴性症状量表（PANSS）评分中的阴性症状显著相关。维生素B6的活性形式吡哆胺是羰基应激的清除剂，可能是治疗这些难治性症状的一种新型有效治疗药物。在本文中，我们描述了一种独特的研究方法，以确定一部分精神分裂症患者病理生理学中的致病过程。我们的发现可能成为这种异质性疾病中精神分裂症亚型分类的基础，并最终带来更有针对性的治疗。
