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In the present work, we studied the paracrine activity of blood cells that could be modulated towards a neuroprotective nature using <jats:italic>in vivo<\/jats:italic> remote conditioning (i.e<jats:italic>.<\/jats:italic> tolerant blood cells). The increased neuronal survival mediated by the tolerant secretome was clearly confirmed <jats:styled-content style=\"fixed-case\"><jats:italic>in vitro<\/jats:italic><\/jats:styled-content> in a model of glutamate toxicity in a primary culture of rat cortical neurons and <jats:italic>in vivo<\/jats:italic> in a pre\u2010 and post\u2010treatment of rats that were subjected to transient occlusion of the middle cerebral artery. Bioinformatic\u2010based analysis of the protein profile revealed higher amounts of proteins released by the tolerant blood cells; 29 proteins were recognised as secreted. More than half of these secreted proteins were involved in the biological processes of the response to the stimulus (GO:0050896) and the response to chemicals (GO:0042221). The protective phenotype was most likely mediated by the synergistic effect of multiple identified proteins, including unique to the tolerant secretome (ceruloplasmin, D\u20103\u2010phosphoglycerate dehydrogenase) and was promoted by the co\u2010participation of several reaction pathways. The most probably of these pathways were post\u2010translation protein modification, MAP2K and MAPK activation and platelet activation. Taken together, our results demonstrate that properly stimulated blood cells could serve as a\u00a0source for cell\u2010free\u2010based therapies of regenerative medicine.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14889-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14889","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T22:59:36Z","timestamp":1570748376000},"page":"99-111","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Rapid remote conditioning mediates modulation of blood cell paracrine activity and leads to the production of a secretome with 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