Hypoxanthine\nProduces Rapid Antidepressant Effects\nby Suppressing Inflammation in Serum and Hippocampus

The occurrence and development of\ndepression are closely related to disorders of the brain and peripheral\nsubstances. Abnormal metabolites in the blood affect the signal regulation\nfunction of the nerve center, which is one of the key factors for\ndepression episodes. This study was focused on metabolites in serum\nand the mechanism of its antidepressant in the hippocampus. In the\npresent study, serum metabolites in patients with depression were\nscreened by metabolomic techniques. Various depressive mouse models\nand behavioral tests were used to assess its antidepressant effects.\nThe expressions of inflammatory signaling were detected by using Western\nblot, ELISA, and immunofluorescence. We found that the metabolite\nhypoxanthine in the serum of patients with depression was significantly\nreduced, and the same result was also found in two mouse models of\ndepression such as chronic unpredictable mild stress (CUMS) and social\ndefeat stress (SD). By administering different doses of hypoxanthine\n(5, 10, 15 mg/kg), we found that only 15 mg/kg was able to significantly\nreduce the latency and increase food consumption in the novelty suppressed-feeding\ntest (NSF), which was also able to reverse the depressive phenotypes\nof mice in the CUMS model after a single administration at 2 h later.\nHypoxanthine obviously reduced the expressions of inflammation in\nserum and downregulated the expressions of MAPK and NLRP3-related\npathways in the hippocampus in CUMS mice. Moreover, hypoxanthine also\nsuppressed the activations of glial cells including GFAP and IBA-1\nin hippocampal CA1, CA3, and dentate gyrus (DG). To sum up, hypoxanthine\nexerted antidepressant effect relying on the inhibition of peripheral\nand hippocampal inflammations by regulating MAPK, NLRP3-related pathways,\nand glial cells. This was the first time that we have found a disordered\nmetabolite in patients with depression and further systematically\ndemonstrated its efficacy and potential mechanism of antidepressants,\nproviding new ideas for antidepressant drug development.