Remote ischemic conditioning modulates inflammatory response and metabolic pathways

Remote ischemic conditioning (RIC) is an endogenous procedure that reduces ischemic injury by repeated transient mechanical obstruction of vessels at a remote limb. However, the specific mechanism of this protective phenomenon remains incompletely understood. We aimed to study perturbations in the brain and plasma metabolome following RIC as well as to identify potential novel inflammatory cytoprotective targets. A mouse model of transient focal cerebral ischemia by compressing the distal middle cerebral artery was used. Multiplex cytokine assay was performed in plasma samples. Blood plasma and brain samples were collected and metabolomes analyzed using non-targeted LC-MS. The analysis revealed a moderate impact on the brain metabolome compared to circulatory metabolites following RIC intervention. Interestingly, 3 plasma metabolites, Cer(42:3), HexCer(36:1) and TG(28:0), stood out as highly significantly upregulated. Moreover, RIC applied during the ischemia (RIPerC) and after the ischemia (RIPostC) protect against cerebral ischemia-reperfusion injury by modulating the peripheral immunomodulation. This study indicated that RIC neuroprotection is present in ischemic mice via the inflammatory response and metabolic changes both in the peripheral blood and ischemic brain.