{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:29:51Z","timestamp":1791473391312,"version":"4.3.4"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T00:00:00Z","timestamp":1709683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obstructive sleep apnea (OSA) is characterized by intermittent repeated episodes of hypoxia\u2013reoxygenation. OSA is associated with cerebrovascular consequences. An enhanced blood\u2013brain barrier (BBB) permeability has been proposed as a marker of those disorders. We studied in mice the effects of 1 day and 15 days intermittent hypoxia (IH) exposure on BBB function. We focused on the dorsal part of the hippocampus and attempted to identify the molecular mechanisms by combining in vivo BBB permeability (Evans blue tests) and mRNA expression of several junction proteins (zona occludens (ZO-1,2,3), VE-cadherin, claudins (1,5,12), cingulin) and of aquaporins (1,4,9) on hippocampal brain tissues. After 15 days of IH exposure we observed an increase in BBB permeability, associated with increased mRNA expressions of claudins 1 and 12, aquaporins 1 and 9. IH seemed to increase early for claudin-1 mRNA expression as it doubled with 1 day of exposure and returned near to its base level after 15 days. Claudin-1 overexpression may represent an immediate response to IH exposure. Then, after 15 days of exposure, an increase in functional BBB permeability was associated with enhanced expression of aquaporin. These BBB alterations are possibly associated with a vasogenic oedema that may affect brain functions and accelerate neurodegenerative processes.<\/jats:p>","DOI":"10.3390\/ijms25053065","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T08:43:14Z","timestamp":1709714594000},"page":"3065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Early Increase in Blood\u2013Brain Barrier Permeability in a Murine Model Exposed to Fifteen Days of Intermittent Hypoxia"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6115-7958","authenticated-orcid":false,"given":"Frederic","family":"Roche","sequence":"first","affiliation":[{"name":"INSERM, SAINBIOSE U1059, Universit\u00e9 Jean Monnet Saint-\u00c9tienne, Mines Saint Etienne, F-42023 Saint-\u00c9tienne, France"},{"name":"INSERM U1300, HP2 Laboratory, Universit\u00e9 Grenoble Alpes, F-38042 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Brian\u00e7on-Marjollet","sequence":"additional","affiliation":[{"name":"INSERM U1300, HP2 Laboratory, Universit\u00e9 Grenoble Alpes, F-38042 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Dematteis","sequence":"additional","affiliation":[{"name":"INSERM U1300, HP2 Laboratory, Universit\u00e9 Grenoble Alpes, F-38042 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Baldazza","sequence":"additional","affiliation":[{"name":"INSERM U1300, HP2 Laboratory, Universit\u00e9 Grenoble Alpes, F-38042 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Gonthier","sequence":"additional","affiliation":[{"name":"INSERM U1300, HP2 Laboratory, Universit\u00e9 Grenoble Alpes, F-38042 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederique","family":"Bertholon","sequence":"additional","affiliation":[{"name":"Centre de Ressources Biologiques, CHU de Saint Etienne, F-42055 Saint-\u00c9tienne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Perek","sequence":"additional","affiliation":[{"name":"INSERM, SAINBIOSE U1059, Universit\u00e9 Jean Monnet Saint-\u00c9tienne, Mines Saint Etienne, F-42023 Saint-\u00c9tienne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3832-2358","authenticated-orcid":false,"given":"Jean-Louis","family":"P\u00e9pin","sequence":"additional","affiliation":[{"name":"INSERM U1300, HP2 Laboratory, Universit\u00e9 Grenoble Alpes, F-38042 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.pcad.2008.08.001","article-title":"Epidemiology, Risk Factors, and Consequences of Obstructive Sleep Apnea and Short Sleep Duration","volume":"51","author":"Patel","year":"2009","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e119","DOI":"10.1161\/CIR.0000000000001082","article-title":"Sleep-Disordered Breathing and Cardiac Arrhythmias in Adults: Mechanistic Insights and Clinical Implications: A Scientific Statement From the American Heart Association","volume":"146","author":"Mehra","year":"2022","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1164\/rccm.201808-1509OC","article-title":"Symptom Subtypes of Obstructive Sleep Apnea Predict Incidence of Cardiovascular Outcomes","volume":"200","author":"Mazzotti","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1007\/s12017-012-8182-1","article-title":"Cognition in Obstructive Sleep Apnea-Hypopnea Syndrome (OSAS): Current Clinical Knowledge and the Impact of Treatment","volume":"14","author":"Kielb","year":"2012","journal-title":"NeuroMolecular Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1183\/09031936.04.00091903","article-title":"Performance vigilance task and sleepiness in patients with sleep-disordered breathing","volume":"24","author":"Sforza","year":"2004","journal-title":"Eur. Respir. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e13803","DOI":"10.1111\/jsr.13803","article-title":"Obstructive sleep apnea-related intermittent hypoxaemia is associated with impaired vigilance","volume":"32","author":"Pahari","year":"2023","journal-title":"J. Sleep Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nrn2762","article-title":"The memory function of sleep","volume":"11","author":"Diekelmann","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/s12967-016-0887-8","article-title":"Longitudinal Brain Structural Alterations and Systemic Inflammation in Obstructive Sleep Apnea before and after Surgical Treatment","volume":"14","author":"Lin","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-0-387-75434-5_5","article-title":"Intermittent Hypoxia and Cognitive Function: Implications from Chronic Animal Models","volume":"618","author":"Row","year":"2007","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.smrv.2012.12.003","article-title":"Obstructive Sleep Apnea and Cognitive Impairment: Addressing the Blood-Brain Barrier","volume":"18","author":"Lim","year":"2014","journal-title":"Sleep Med. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-med-042915-102623","article-title":"Obstructive Sleep Apnea: Update and Future","volume":"68","author":"Lim","year":"2017","journal-title":"Annu. Rev. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1073\/pnas.96.2.511","article-title":"Claudin Multigene Family Encoding Four-Transmembrane Domain Protein Components of Tight Junction Strands","volume":"96","author":"Morita","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12987-019-0123-z","article-title":"Claudin-5: Gatekeeper of Neurological Function","volume":"16","author":"Greene","year":"2019","journal-title":"Fluids Barriers CNS"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1083\/jcb.200302070","article-title":"Size-Selective Loosening of the Blood-Brain Barrier in Claudin-5-Deficient Mice","volume":"161","author":"Nitta","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1523\/JNEUROSCI.1432-18.2018","article-title":"Claudin-1-Dependent Destabilization of the Blood-Brain Barrier in Chronic Stroke","volume":"39","author":"Sladojevic","year":"2019","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nrn3468","article-title":"Aquaporin Water Channels in the Nervous System","volume":"14","author":"Papadopoulos","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/0955-0674(95)80003-4","article-title":"Aquaporin Water Channels: Unanswered Questions and Unresolved Controversies","volume":"7","author":"Agre","year":"1995","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1038\/s41598-023-29894-1","article-title":"The Tight Junction Protein Occludin Modulates Blood-Brain Barrier Integrity and Neurological Function after Ischemic Stroke in Mice","volume":"13","author":"Sugiyama","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1152\/physrev.00019.2012","article-title":"Claudins and the Modulation of Tight Junction Permeability","volume":"93","author":"Yu","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1083\/jcb.147.6.1351","article-title":"Direct Binding of Three Tight Junction-Associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH Termini of Claudins","volume":"147","author":"Itoh","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S0750-7658(03)00010-8","article-title":"[Brain oedema following blood-brain barrier disruption: Mechanisms and diagnosis]","volume":"22","author":"Payen","year":"2003","journal-title":"Ann. Fr. Anesth. Reanim."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.3171\/2009.8.JNS081704","article-title":"Aquaporin-1-Mediated Cerebral Edema Following Traumatic Brain Injury: Effects of Acidosis and Corticosteroid Administration","volume":"112","author":"Tran","year":"2010","journal-title":"J. Neurosurg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.resp.2012.10.012","article-title":"Altered Aquaporins in the Brains of Mice Submitted to Intermittent Hypoxia Model of Sleep Apnea","volume":"185","author":"Baronio","year":"2013","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.5665\/sleep.5042","article-title":"Chronic Intermittent Hypoxia Induces Chronic Low-Grade Neuroinflammation in the Dorsal Hippocampus of Mice","volume":"38","author":"Sapin","year":"2015","journal-title":"Sleep"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1152\/physrev.00050.2017","article-title":"Blood-Brain Barrier: From Physiology to Disease and Back","volume":"99","author":"Sweeney","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.brainres.2014.11.052","article-title":"Hypomyelination, Memory Impairment, and Blood-Brain Barrier Permeability in a Model of Sleep Apnea","volume":"1597","author":"Kim","year":"2015","journal-title":"Brain Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s00401-011-0883-2","article-title":"Claudin-1 induced sealing of blood-brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis","volume":"122","author":"Pfeiffer","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/S0014-5793(03)01083-4","article-title":"Aquaporin Water Channels: Molecular Mechanisms for Human Diseases","volume":"555","author":"Agre","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/sj.bjc.6600512","article-title":"Increased Aquaporin 1 Water Channel Expression in Human Brain Tumours","volume":"87","author":"Saadoun","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C529","DOI":"10.1152\/ajpcell.00408.2003","article-title":"Expression of the AQP-1 Water Channel in Normal Human Tissues: A Semiquantitative Study Using Tissue Microarray Technology","volume":"286","author":"Mobasheri","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.brainres.2015.03.004","article-title":"Aquaporins and Blood-Brain Barrier Permeability in Early Edema Development after Traumatic Brain Injury","volume":"1611","author":"Blixt","year":"2015","journal-title":"Brain Res."},{"key":"ref_32","first-page":"705","article-title":"Greatly Improved Survival and Neuroprotection in Aquaporin-4-Knockout Mice Following Global Cerebral Ischemia","volume":"28","author":"Katada","year":"2014","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12987-019-0150-9","article-title":"Claudin-12 Is Not Required for Blood-Brain Barrier Tight Junction Function","volume":"16","author":"Coisne","year":"2019","journal-title":"Fluids Barriers CNS"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chatard, M., Puech, C., Roche, F., and Perek, N. (2016). Hypoxic Stress Induced by Hydralazine Leads to a Loss of Blood-Brain Barrier Integrity and an Increase in Efflux Transporter Activity. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158010"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Voirin, A.C., Chatard, M., Brian\u00e7on-Marjollet, A., Pepin, J.L., Perek, N., and Roche, F. (2023). Loss of Blood-Brain Barrier Integrity in an In Vitro Model Subjected to Intermittent Hypoxia: Is Reversion Possible with a HIF-1\u03b1 Pathway Inhibitor?. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24055062"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1159\/000479399","article-title":"Hydralazine Is a Suitable Mimetic Agent of Hypoxia to Study the Impact of Hypoxic Stress on In Vitro Blood-Brain Barrier Model","volume":"42","author":"Chatard","year":"2017","journal-title":"Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.33594\/000000311","article-title":"Intermittent Hypoxia and Its Impact on Nrf2\/HIF-1\u03b1 Expression and ABC Transporters: An in Vitro Human Blood-Brain Barrier Model Study","volume":"54","author":"Zolotoff","year":"2020","journal-title":"Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11309","DOI":"10.1038\/s41598-020-68374-8","article-title":"Sera of Elderly Obstructive Sleep Apnea Patients Alter Blood-Brain Barrier Integrity in Vitro: A Pilot Study","volume":"10","author":"Voirin","year":"2020","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/3065\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:09:54Z","timestamp":1760105394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/3065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,6]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25053065"],"URL":"https:\/\/doi.org\/10.3390\/ijms25053065","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,6]]}}}