Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Psychiatry Research, Stockholm City Council, Stockholm, Sweden; Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland.
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; Neuroscience Center, University of Helsinki, Helsinki, Finland.
Schizophr Res. 2021 Jun;232:33-41. doi: 10.1016/j.schres.2021.05.011. Epub 2021 May 16.
The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA-related pathway, compared to those time periods when the same individual did not use the drug. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA-related purine, oxidative stress, and glutamatergic signaling pathways are among primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists - which have shown beneficial effects in an experimental Adcyap1 mouse model for schizophrenia - could be potential treatments even before the full manifestation of illness involving dopaminergic abnormalities.
精神分裂症的分子病理生理机制仍然未知，也没有针对原发性预防的治疗方法。我们使用Ingenuity Pathway Analysis 分析了两个不同数据集（包括来自芬兰和美国的患者）中的经典和因果途径。在芬兰数据集中，经典途径分析中最显著的发现是谷氨酸受体信号转导、肝纤维化和糖蛋白 6 (GP6)途径，而美国数据集中则是 GP6 和肝纤维化途径。在数据驱动的因果途径中，ADCYAP1、ADAMTS 和 CACNA 基因参与了芬兰和美国数据集区分患者和对照的前 10 条途径中的大多数。来自芬兰全国性数据库的结果表明，与同一时期未使用该药物相比，在使用洛沙坦（ADCYAP1、ADAMTS 和 CACNA 相关途径的主要调节剂）的首发精神分裂症患者中，精神分裂症复发的风险降低了 41%。两个独立数据集的结果表明，GP6 信号通路以及与 ADCYAP1、ADAMTS 和 CACNA 相关的嘌呤、氧化应激和谷氨酸能信号通路是欧洲血统精神分裂症患者的主要病理生理改变之一。虽然没有观察到可重复的多巴胺能改变，但结果表明，洛沙坦和 ADCYAP1/PACAP 缺陷缓解剂（如代谢型谷氨酸 2/3 激动剂 MGS0028 和 5-HT7 拮抗剂）等药物可能是潜在的治疗方法，甚至在涉及多巴胺能异常的疾病完全表现之前也是如此。
