{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:40:19Z","timestamp":1785404419659,"version":"3.56.0"},"reference-count":126,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:00:00Z","timestamp":1781913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["25-25-00101"],"award-info":[{"award-number":["25-25-00101"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["25-25-00101"],"award-info":[{"award-number":["25-25-00101"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recovery after an ischemic stroke depends not only on neuronal survival but also on inflammatory mechanisms that determine secondary injury and reparative plasticity. This review summarizes the evidence on hypoxic conditioning, permissive hypercapnia, and their combined application as modulators of neuroinflammation and neurorehabilitation. This review does not aim to describe the fundamental mechanisms of neuroinflammation, but rather to examine how hypoxia, hypercapnia, and their interaction provide potential targets for its modulation. Prolonged or severe hypoxia exacerbates neuroinflammation through NF-\u03baB activation, NLRP3 inflammasome signaling, pro-inflammatory cytokine production, and microglial activation. In contrast, controlled intermittent hypoxia in pre-\/postconditioning protocols suppresses inflammatory processes, promotes reparative microglial phenotypes, activates PI3K\/Akt-dependent survival pathways, and modulates the fractalkine\/CX3CR1 axis. Permissive hypercapnia also has context-dependent immunomodulatory properties: moderate exposure may reduce NF-\u03baB-driven inflammation, oxidative damage, apoptosis, and blood\u2013brain barrier disruption, whereas prolonged hypercapnia, especially with hypoxemia, may enhance inflammasome activation and microglial reactivity. Therefore, combined intermittent hypercapnic hypoxia may act as a therapeutic stimulus integrating anti-inflammatory, cytoprotective, barrier-stabilizing, and neuroplastic mechanisms. Clinical evidence regarding ischemic stroke and cerebral palsy is encouraging but limited. Future studies should determine optimal gas exposure protocols, precisely define the mechanisms underlying the anti-inflammatory effects, and establish whether pharmacological potentiation using modulators of the NLRP3, PI3K\/Akt, BDNF\/TrkB, and JNK signaling pathways is feasible.<\/jats:p>","DOI":"10.3390\/ijms27125579","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:09:17Z","timestamp":1782270557000},"page":"5579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular and Cellular Signaling Pathways of the Effects of Hypoxia and Hypercapnia on the Mechanisms of Neuroinflammation"],"prefix":"10.3390","volume":"27","author":[{"given":"Pavel A.","family":"Chekulaev","sequence":"first","affiliation":[{"name":"Brain Science Institute, Russian Center of Neurology and Neurosciences, 125367 Moscow, Russia"},{"name":"Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgy M.","family":"Zembatov","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Russian Center of Neurology and Neurosciences, 125367 Moscow, Russia"},{"name":"Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia D.","family":"Namiot","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Russian Center of Neurology and Neurosciences, 125367 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana M.","family":"Alekseeva","sequence":"additional","affiliation":[{"name":"V.A. Almazov National Medical Research Center, 197341 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan K.","family":"Ternovykh","sequence":"additional","affiliation":[{"name":"V.A. Almazov National Medical Research Center, 197341 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaripat S.","family":"Manasova","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4869-5465","authenticated-orcid":false,"given":"Vladimir P.","family":"Kulikov","sequence":"additional","affiliation":[{"name":"Department of Ultrasound and Functional Diagnostics, Altay State Medical University, 656040 Barnaul, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5425-7707","authenticated-orcid":false,"given":"Natalia S.","family":"Andriutsa","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3650-6121","authenticated-orcid":false,"given":"Pavel P.","family":"Tregub","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Russian Center of Neurology and Neurosciences, 125367 Moscow, Russia"},{"name":"Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"},{"name":"Scientific and Educational Resource Center \u201cInnovative Technologies of Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis\u201d, RUDN University, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yuan, H., Liu, J., Gu, Y., Ji, X., and Nan, G. (2022). 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