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Although its protective effects are recognized, the underlying mechanisms remain incompletely understood. This study investigated the metabolic and inflammatory changes induced by RIC to identify novel cytoprotective targets. We used a mouse model of transient focal cerebral ischemia induced by 60-min occlusion of the distal middle cerebral artery. Two RIC protocols were applied: remote ischemic perconditioning (RIPerC), consisting of three cycles of 5-min hindlimb ischemia followed by 5-min reperfusion during ischemia, and remote ischemic postconditioning (RIPostC), applied after reperfusion. Plasma cytokines were quantified using a multiplex assay, and metabolomic profiles of plasma and brain samples were analyzed by untargeted liquid chromatography\u2013mass spectrometry (LC\u2013MS). Data were evaluated with univariate and multivariate statistical methods. RIC induced moderate changes in the brain metabolome but significantly increased three plasma metabolites: Cer (42:3), HexCer (36:1), and TG (28:0), suggesting systemic metabolic modulation during ischemia-reperfusion. Both RIPerC and RIPostC conferred neuroprotection, likely through regulation of peripheral immune responses. These findings demonstrate that RIPerC and RIPostC protect against ischemic injury by modulating inflammatory and metabolic pathways in systemic circulation and brain, providing insights into ischemic tolerance and biomarker discovery.<\/jats:p>","DOI":"10.1177\/0271678x261458135","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T06:32:26Z","timestamp":1780295546000},"page":"2461-2478","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Remote ischemic perconditioning and postconditioning reduced cerebral ischemic injury modulating inflammatory responses and metabolic pathways"],"prefix":"10.1177","volume":"46","author":[{"given":"Coral","family":"Torres-Querol","sequence":"first","affiliation":[{"name":"Clinical Neurosciences Group, Institut de Recerca Biom\u00e8dica de Lleida, Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinald","family":"Pamplona","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Lleida Biomedical Research Institute, University of Lleida, Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Arqu\u00e9","sequence":"additional","affiliation":[{"name":"Clinical Neurosciences Group, Institut de Recerca Biom\u00e8dica de Lleida, Lleida, Spain"},{"name":"Psychology Department, Universitat de Lleida, Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1808-5968","authenticated-orcid":false,"given":"Francisco","family":"Purroy","sequence":"additional","affiliation":[{"name":"Clinical Neurosciences Group, Institut de Recerca Biom\u00e8dica de Lleida, Lleida, Spain"},{"name":"Stroke Unit, Department of Neurology, Hospital Universitari Arnau de Vilanova, Lleida, Spain"},{"name":"Department of Medicine and Surgery, Universitat de Lleida, Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.74.5.1124"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.94.9.2193"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.223"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-03003-6"},{"key":"e_1_3_3_6_2","article-title":"RIC-specific cytoprotective profile mediated by microglia in a mouse model of acute ischaemic stroke","volume":"2025","author":"Torres-Querol C","year":"2025","unstructured":"Torres-Querol C, Arque G, Purroy F. 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