Depression, insulin resistance and xanthurenic acid in hepatitis C virus patients

描述（由申请人提供）：丙型肝炎病毒是最常见的血源性感染，也是肝硬化和肝癌的主要原因，其特点是干扰素(IFN)- α治疗的副作用导致30 - 50%的抑郁症，并且胰岛素抵抗（IR）的发生率同样高，是2型糖尿病的危险因素。慢性炎症被认为是抑郁症和IR的共同特征。慢性、Th-1型炎症对抑郁和IR影响的分子机制尚不清楚。本研究旨在探讨黄嘌呤酸（XA）形成上调与ifn - α诱导的抑郁和IR相关的可能性。促炎因子（如IFN）下调色氨酸（TRP）转化为血清素（一种抗抑郁作用的主要靶点），上调色氨酸代谢为犬尿氨酸（KYN），后者是生成3-羟基KYN （HK）的底物，是XA的前体。重度抑郁症患者XA尿量增加，血清HK升高，而XA的正常化预示着康复。HK进一步代谢形成NAD+，依赖于吡哆醛'-5-磷酸（P5P）。炎症降低了P5P的可用性，因此，将过量产生的HK从NAD+的形成转向XA的产生。XA致糖尿病作用的可能机制可能包括通过caspase 3依赖性机制诱导胰腺β细胞的病理性凋亡。我们的工作假设表明，XA的上调形成是与ifn - α诱导的抑郁和IR相关的标志物。我们在60例HCV患者中观察到IR和血清KYN之间的相关性（r=0.32, p=0.01），部分支持了这一观点。然而，我们没有评估HK， XA和P5P，并且没有足够的样本来评估XA和IR与抑郁症的相关性。作为一项概念验证的试点研究，我们建议在已经收集的300名HCV参与者的血液样本中评估IFNG(+874)T/ a基因多态性在ifn - α诱导的抑郁症中的作用，评估IR、XA（以及TRP、KYN和KYNA）和P5P。获得的结果将与我们已经收集的关于ifn - α诱导的抑郁症发生率和血清新蝶呤水平的数据合并，新蝶呤是ifn相关炎症的标志物，正如我们之前报道的那样，与IR相关，与P5P相反。我们将分析这些标志物之间的关联，以及与ifn - α诱导的抑郁症的发生率之间的关联。我们预测XA和IR之间的正相关关系，以及XA和ifn - α相关抑郁症的可能性之间的正相关关系。我们还期望XA、IR和P5P之间呈负相关。这项初步研究的结果将有助于开发新的工具，用于预防/治疗HCV患者的抑郁症和2型糖尿病，以及与慢性炎症和（如重度抑郁症、代谢综合征、肥胖和衰老）相关的其他疾病。

DESCRIPTION (provided by applicant): Hepatitis C virus, the most common blood-borne infection and a major cause of liver cirrhosis and carcinoma, is characterized by a 30 - 50% rate of depression as a side-effect of interferon (IFN)-alpha therapy, and by similarly high incidence of insulin resistance (IR), diabetes type 2 risk factor. Chronic inflammation was suggested as a common denominator for both depression and IR. Molecular mechanisms mediating impact of chronic, Th-1 type, inflammation on depression and IR are not clear. This proposal aims to explore the possibility that up-regulated formation of xanthurenic acid (XA) is associated with both IFN-alpha induced depression and IR. Pro-inflammatory factors (e.g., IFN) down-regulate tryptophan (TRP) conversion into serotonin, a major target of antidepressant action, and up-regulate TRP metabolism into kynurenine (KYN), a substrate for production of 3-hydroxyKYN (HK), a precursor of XA. Increased urine excretion of XA, and elevated serum HK were observed in major depressive disorder while normalization of XA predicted the recovery. Further metabolism of HK towards NAD+ formation, depends on pyridoxal'-5-phosphate (P5P). Inflammation reduces availability of P5P, and, thus, diverts excessively produced HK from formation of NAD+ towards production of XA. Possible mechanisms of diabetogenic effects of XA might include , an induction of pathological apoptosis of pancreatic beta cells through caspase 3-dependent mechanism. Our working hypothesis suggests that up-regulated formation of XA is a marker associated with both IFN-alpha induced depression and IR. This suggestion is partly supported by our observation of correlation (r=0.32, p=0.01) between IR and serum KYN in 60 HCV patients. However, we did not assess HK, XA and P5P, and had not enough samples to assess the correlation of XA and IR with depression. As a proof-of-concept pilot study we propose to evaluate IR, XA (and TRP, KYN and KYNA), and P5P in already collected blood samples of 300 HCV participants of our completed R21 study of IFNG(+874)T/A gene polymorphisms in IFN-alpha induced depression. Obtained results will be merged with our already collected data on incidence of IFN-alpha induced depression and serum levels of neopterin, a marker of IFN-related inflammation, that, as we reported previously,, correlates with IR and, inversely, with P5P. We will analyze associations of these markers with each other, and also with incidence of IFN-alpha induced depression. We predict positive correlations between XA and IR, and also between XA and the likelihood of having IFN-alpha associated depression. We also expect inverse correlations between XA and IR and P5P. Results of this pilot study will help to develop new tools for prevention/treatment of depression and type 2 diabetes in HCV and other conditions associated with chronic inflammation and (e.g., major depressive disorder, metabolic syndrome, obesity and aging).