Abstract P2115: (2R,6R)-Hydroxynorketamine Prevents Myocardial Ischemia Reperfusion Injury By Regulating Immune And Inflammatory Response

Background: The ketamine metabolite 2R,6R-hydroxynorketamine (HNK) has recently attracted increasing attention by its potential as a novel fast-acting antidepressant candidate to treat depression. HNK has anti-inflammatory properties which contribute to its protective effects against ischemia and reperfusion (I/R) injury. However, whether HNK produces beneficial effects on myocardial I/R injury has not been elucidated yet. Here we tested the hypothesis that HNK might protects the heart from myocardial I/R injury by limiting myocardial inflammation. Methods and Results: Twelve male C57BL/6J mice (8-10 weeks old, 20-25 g) were used to produce acute myocardial I/R (30 min/24 h) by micro-surgery. Mice were divided into four groups: Sham, HNK+Sham, I/R, HNK+I/R. A single-dose of HNK (30 mg/kg) was intraperitoneally injected one hour before the I/R. Echocardiographic imaging and TTC staining showed that HKN administration before myocardial I/R increased fraction shortening by 26.5% and limited infarct size by 40% compared to I/R alone. Proteomics analysis showed HNK caused 81 proteins down-regulated and 18 proteins up-regulated in the left ventricle after I/R (HNK+I/R vs . I/R). The gene name of the top 5 down-regulated proteins are Ighg2b, Igkv17-121, Igkc, Igtp and Cd68. The go enrichment analysis showed that HNK in the I/R group could modulate immune response via downregulating signal transducer and activation of transcription 1 and 2 (STAT1 and STAT2) and type 1 interferon pathway. The KEGG enrichment analysis showed that HNK affected antigen processing and presentation via down-regulating beta-2-microglobulin, TAPBP and TAP1/2. Cytokine analysis showed that HNK attenuated the increased tissue levels of TNF-alpha, IL-1 beta, CTnI and BNP induced by I/R. HNK also significantly decreased I/R induced-neutrophil infiltration, apoptosis and oxidative stress in the myocardium as detected by Ly6G staining, tunel staining and DHE probe staining. Conclusion: We demonstrated for the first time the administration of HNK regulates immune response through STAT1 and STAT2 and type 1 interferon pathway in the heart, leading to the cardioprotection against I/R injury. The use of HNK may become an immunomodulatory therapy for the ischemic heart disease.