Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, SA, Australia.
Transl Psychiatry. 2024 Oct 17;14(1):439. doi: 10.1038/s41398-024-03157-7.
There is increasing interest in the pathophysiological role of arginine metabolism in schizophrenia, particularly in relation to the modulation of the endogenous messenger nitric oxide (NO). The assessment of specific arginine metabolites that, unlike NO, are stable can provide useful insights into NO regulatory enzymes such as isoform 1 of dimethylarginine dimethylaminohydrolase (DDAH1) and arginase. We investigated the role of arginine metabolomics in schizophrenia by conducting a systematic review and meta-analysis of the circulating concentrations of arginine metabolites associated with DDAH1, arginase, and NO synthesis [arginine, citrulline, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), dimethylamine, and ornithine] in this patient group. We searched PubMed, Scopus, and Web of Science from inception to the 31 of May 2023 for studies investigating arginine metabolites in patients with schizophrenia and healthy controls. The JBI Critical Appraisal Checklist for analytical studies and GRADE were used to assess the risk of bias and the certainty of evidence, respectively (PROSPERO registration number: CRD42023433000). Twenty-one studies were identified for analysis. There were no significant between-group differences in arginine, citrulline, and SDMA. By contrast, patients with schizophrenia had significantly higher ADMA (DDAH1 substrate, standard mean difference, SMD = 1.23, 95% CI 0.86-1.61, p < 0.001; moderate certainty of evidence), dimethylamine (DDAH1 product, SMD = 0.47, 95% CI 0.24-0.70, p < 0.001; very low certainty of evidence), and ornithine concentrations (arginase product, SMD = 0.32, 95% CI 0.16-0.49, p < 0.001; low certainty of evidence). In subgroup analysis, the pooled SMD for ornithine was significantly different in studies of untreated, but not treated, patients. Our study suggests that DDAH1 and arginase are dysregulated in schizophrenia. Further studies are warranted to investigate the expression/activity of these enzymes in the brain of patients with schizophrenia and the effects of targeted treatments.
人们对精氨酸代谢在精神分裂症中的病理生理作用越来越感兴趣，特别是在调节内源性信使一氧化氮 (NO) 方面。评估特定的精氨酸代谢物，与 NO 不同，它们是稳定的，可以为 NO 调节酶（如二甲基精氨酸二甲氨基水解酶 1 型（DDAH1）和精氨酸酶）提供有用的见解。我们通过对与 DDAH1、精氨酸酶和 NO 合成相关的循环浓度进行系统评价和荟萃分析，研究了精氨酸代谢组学在精神分裂症中的作用 [精氨酸、瓜氨酸、不对称二甲基精氨酸 (ADMA)、对称二甲基精氨酸 (SDMA)、二甲胺和鸟氨酸] 在该患者组中。我们从建立到 2023 年 5 月 31 日，在 PubMed、Scopus 和 Web of Science 上搜索了研究精神分裂症患者和健康对照者精氨酸代谢物的研究。使用 JBI 分析研究的批判性评价清单和 GRADE 分别评估偏倚风险和证据确定性（PROSPERO 注册号：CRD42023433000）。确定了 21 项研究进行分析。在精氨酸、瓜氨酸和 SDMA 方面，两组之间没有显著差异。相比之下，精神分裂症患者的 ADMA（DDAH1 底物，标准均数差，SMD=1.23，95%CI 0.86-1.61，p<0.001；中等确定性证据）、二甲胺（DDAH1 产物，SMD=0.47，95%CI 0.24-0.70，p<0.001；极低确定性证据）和鸟氨酸浓度（精氨酸酶产物，SMD=0.32，95%CI 0.16-0.49，p<0.001；低确定性证据）明显更高。在亚组分析中，未治疗但未治疗的患者研究中，鸟氨酸的汇总 SMD 差异具有统计学意义。我们的研究表明，DDAH1 和精氨酸酶在精神分裂症中失调。需要进一步研究以调查精神分裂症患者大脑中这些酶的表达/活性以及靶向治疗的效果。
