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

描述(申请人提供)：丙型肝炎病毒是最常见的血液传播感染，也是肝硬变和癌症的主要原因，其特点是干扰素(干扰素)-α治疗的副作用导致30-50%的抑郁率，以及类似的胰岛素抵抗(IR)和2型糖尿病的高风险因素。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。这一建议旨在探索黄原酸(XA)的上调形成是否与干扰素-α诱导的抑郁和IR有关。促炎因子(如干扰素)下调色氨酸(Trp)转化为5-羟色胺(抗抑郁作用的主要靶点)，并上调Trp代谢为犬尿氨酸(KYN)，KYN是产生XA前体3-羟基KYN(HK)的底物。重度抑郁障碍患者尿中XA排泄量增加，血清HK升高，而XA正常者预示病情恢复。HK向NAD+的进一步代谢依赖于吡哆醛-5-磷酸(P5P)。炎症减少了P5P的可获得性，从而将过量产生的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caspase3依赖的机制诱导胰岛β细胞病理性凋亡。我们的工作假说表明，XA的上调形成是与干扰素-α诱导的抑郁和IR相关的一个标志。我们在60例丙型肝炎患者中观察到IR与血清KYN的相关性(r=0.32，p=0.01)，这部分支持了这一观点。然而，我们没有评估HK、XA和P5P，也没有足够的样本来评估XA和IR与抑郁的相关性。作为一项概念验证先导性研究，我们建议评估已经收集的300名丙型肝炎患者的血液样本中的IR、XA(以及Trp、Kyn和KYNA)和P5P，这些样本是我们完成的关于干扰素-α诱导的抑郁症中IFNG(+874)T/A基因多态的R21研究。获得的结果将与我们已经收集的关于干扰素-α诱导的抑郁发生率和血清新喋呤水平的数据合并在一起，新喋呤是干扰素相关炎症的标志，正如我们之前报道的那样，它与IR相关，与P5P相反。我们将分析这些标记物之间的相互关系，以及与干扰素-α诱导的抑郁发生率的关系。我们预测XA和IR之间以及XA和干扰素-α相关抑郁症的可能性之间存在正相关。我们还预计XA与IR和P5P之间存在负相关。这项初步研究的结果将有助于开发新的工具，用于预防/治疗丙型肝炎患者的抑郁和2型糖尿病，以及与慢性炎症和(例如，严重抑郁障碍、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).