Disrupted NAD(P) Metabolism and Xanthine Dehydrogenase in a Stress-Induced Rat Model of Depression: NMR Metabolomics Insights

<b>Background</b>: Clinical findings have shown a negative correlation between the severity of depressive symptoms and serum uric acid levels in men, yet the role of metabolic regulation in the pathophysiology of depression remains largely unknown. <b>Methods</b>: In this study, we utilized an acute restraint-stress-induced male rat model of depression to investigate biochemical changes through NMR-based metabolomics combined with serum biochemical analysis. Additionally, we employed qPCR, immunoblotting, and enzyme activity assays to assess the expression and activity of xanthine oxidoreductase, the rate-limiting enzyme in uric acid production. <b>Results</b>: Our findings indicate the following: (1) restraint stress is a valid method for inducing a depressive phenotype in rats; (2) depressive rats exhibit decreased NAD(P) levels in the liver and increased nicotinamide <i>N</i>-oxide and nicotinate levels in urine, accompanied by decreased levels of uric acid, allantoin, and allantoic acid in serum or tissues; (3) xanthine dehydrogenase activity is diminished in depressive rats without corresponding changes in gene or protein expression. <b>Conclusion</b>: The increased urinary excretion of NAD(P) precursors results in reduced hepatic NAD(P) levels, thereby suppressing NAD-dependent xanthine dehydrogenase activity and diminishing the production of uric acid and its downstream metabolites (allantoin and allantoic acid).