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Its complexity poses significant challenges for effective diagnostics and treatments, highlighting the need for novel animal models and comprehensive BBB dysfunction studies. This study investigates chronic BBB dysfunction induction using osmotic disruption via mannitol in healthy adult male Sprague Dawley rats over 12 weeks. Group 1 received 1 bolus\/week (2.0 g\/kg), Group 2 received 3 boluses\/week (1.5 g\/kg), and Group 3 received 3 boluses\/week (2.5 g\/kg). BBB dysfunction was assessed using gadolinium (Gd) infusion and MRI to evaluate location, severity, evolution, and persistence. MR spectroscopy (MRS) examined the brain metabolism changes due to intravenous mannitol, with T2-weighted MRI assessing brain lesions. Biomarkers of neuroinflammation were analyzed in the highest mannitol dose group. Our data show chronic BBB dysfunction primarily in the cortex, hippocampus, and striatum, but not in the corpus callosum of rats under periodic mannitol dosing in groups 1 and 2. MRS identified a distinctive metabolite signature, including changes in alanine, choline, and N-acetyl aspartate in the striatum of Group 1. No significant differences were found in the serum levels of all pro- and anti-inflammatory cytokines analyzed in the high-dose Group 3. This study underscores the feasibility and implications of using osmotic disruption to model chronic BBB dysfunction, offering insights for future neuroprotection and therapeutic strategies research.<\/jats:p>","DOI":"10.3390\/ijms25189792","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T09:10:57Z","timestamp":1725959457000},"page":"9792","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Assessment of Mannitol-Induced Chronic Blood\u2013Brain Barrier Dysfunction In Vivo Using Magnetic Resonance"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8482-3893","authenticated-orcid":false,"given":"Ana","family":"Sampedro-Viana","sequence":"first","affiliation":[{"name":"Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Hospital Cl\u00ednico Universitario, R\u00faa Travesa da Choupana s\/n, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabela","family":"Fern\u00e1ndez-Rodicio","sequence":"additional","affiliation":[{"name":"Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Hospital Cl\u00ednico Universitario, R\u00faa Travesa da Choupana s\/n, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Castillo","sequence":"additional","affiliation":[{"name":"Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Hospital Cl\u00ednico Universitario, R\u00faa Travesa da Choupana s\/n, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1249-6333","authenticated-orcid":false,"given":"Pablo","family":"Hervella","sequence":"additional","affiliation":[{"name":"Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Hospital Cl\u00ednico Universitario, R\u00faa Travesa da Choupana s\/n, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2603-5271","authenticated-orcid":false,"given":"Mar\u00eda Luz","family":"Alonso-Alonso","sequence":"additional","affiliation":[{"name":"Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Hospital Cl\u00ednico Universitario, R\u00faa Travesa da Choupana s\/n, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9985-9135","authenticated-orcid":false,"given":"Ram\u00f3n","family":"Iglesias-Rey","sequence":"additional","affiliation":[{"name":"Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Hospital Cl\u00ednico Universitario, R\u00faa Travesa da Choupana s\/n, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s00401-018-1815-1","article-title":"Functional morphology of blood-brain barrier in health and disease","volume":"135","author":"Liebner","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/2045-8118-9-23","article-title":"Tight junctions at the blood brain barrier: Physiological architecture and disease-associated dysregulation","volume":"9","author":"Artus","year":"2012","journal-title":"Fluids Barriers CNS"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.cell.2015.10.067","article-title":"Establishment and Dysfunction of the BBB","volume":"163","author":"Zhen","year":"2015","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12987-020-00192-6","article-title":"Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood-brain barrier model","volume":"17","author":"Curtaz","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.stemcr.2017.02.021","article-title":"Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells","volume":"8","author":"Cubukova","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sanchez-Varo, R., Mejias-Ortega, M., Fernandez-Valenzuela, J.J., Nu\u00f1ez-Diaz, C., Caceres-Palomo, L., Vegas-Gomez, L., Sanchez-Mejias, E., Trujillo-Estrada, L., Garcia-Leon, J.A., and Moreno-Gonzalez, I. (2022). Transgenic Mouse Models of Alzheimer\u2019s Disease: An Integrative Analysis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105404"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yokoyama, M., Kobayashi, H., Tatsumi, L., and Tomita, T. (2022). Mouse Models of Alzheimer\u2019s Disease. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.912995"},{"key":"ref_8","first-page":"274","article-title":"Streptozotocin as a tool for induction of rat models of diabetes: A practical guide","volume":"22","author":"Ghasemi","year":"2023","journal-title":"EXCLI J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/s12974-015-0434-1","article-title":"Lipopolysaccharide-induced blood-brain barrier disruption: Roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit","volume":"12","author":"Banks","year":"2015","journal-title":"J. Neuroinflammation"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yan, B.C., Xu, P., Gao, M., Wang, J., Jiang, D., Zhu, X., Won, M.H., and Su, P.Q. (2018). Changes in the Blood-Brain Barrier Function Are Associated With Hippocampal Neuron Death in a Kainic Acid Mouse Model of Epilepsy. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.00775"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.ejphar.2015.03.042","article-title":"Animal models of Multiple Sclerosis","volume":"759","author":"Procaccini","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Van Vilet, E.A., Ndode-Ekane, X.E., Lehto, L.J., Gorter, J.A., Andrade, P., Aronica, E., Gr\u00f6hn, O., and Pitk\u00e4nen, A. (2020). Long-lasting blood-brain barrier dysfunction and neuroinflammation after traumatic brain injury. Neurobiol. Dis., 145.","DOI":"10.1016\/j.nbd.2020.105080"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Alonso-Alonso, M.L., P\u00e9rez-Mato, M., Sampedro-Viana, A., Correa-Paz, C., \u00c1vila-G\u00f3mez, P., Sobrino, T., Campos, F., Castillo, J., Iglesias-Rey, R., and Hervella, P. (2022). Fibrin-Targeted Nanoparticles for Finding, Visualizing and Characterizing Blood Clots in Acute Ischemic Stroke. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14102156"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jones, L.D., Jackson, J.W., and Maggirwar, S.B. (2016). Modeling HIV-1 Induced Neuroinflammation in Mice: Role of Platelets in Mediating Blood-Brain Barrier Dysfunction. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151702"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Xie, J., Shen, Z., Anraku, Y., Kataoka, K., and Chen, X. (2019). Nanomaterial-based blood-brain-barrier (BBB) crossing strategies. Biomaterials, 224.","DOI":"10.1016\/j.biomaterials.2019.119491"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"599","DOI":"10.3171\/jns.2000.92.4.0599","article-title":"In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans","volume":"92","author":"Siegal","year":"2000","journal-title":"J. Neurosurg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s11060-010-0466-4","article-title":"Inconsistent blood brain barrier disruption by intraarterial mannitol in rabbits: Implications for chemotherapy","volume":"104","author":"Joshi","year":"2011","journal-title":"J. Neurooncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1093\/brain\/awl318","article-title":"Blood\u2013brain barrier leakage may lead to progression of temporal lobe epilepsy","volume":"130","author":"Redeker","year":"2007","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1023\/A:1007049806660","article-title":"Osmotic opening of the blood-brain barrier: Principles, mechanism, and therapeutic applications","volume":"20","author":"Rapoport","year":"2000","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1177\/0271678X19867980","article-title":"Modeling hyperosmotic blood\u2013brain barrier opening within human tissue-engineered in vitro brain microvessels","volume":"40","author":"Linville","year":"2020","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"162","DOI":"10.13004\/kjnt.2023.19.e25","article-title":"Optimizing Mannitol Use in Managing Increased Intracranial Pressure: A Comprehensive Review of Recent Research and Clinical Experiences","volume":"19","author":"Kim","year":"2023","journal-title":"Korean J. Neurotrauma"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"242","DOI":"10.3177\/jnsv.55.242","article-title":"Mannitol lowers fat digestibility and body fat accumulation in both normal and cecectomized rats","volume":"55","author":"Nishiyma","year":"2009","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.nbd.2013.11.019","article-title":"Longitudinal assessment of blood\u2013brain barrier leakage during epileptogenesis in rats. A quantitative MRI study","volume":"63","author":"Otte","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/epi.13246","article-title":"Blood\u2013brain barrier leakage after status epilepticus in rapamycin-treated rats I: Magnetic resonance imaging","volume":"57","year":"2016","journal-title":"Epilepsia"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yen, L.F., Wei, V.C., Kuo, E.Y., and Lai, T.W. (2013). Distinct Patterns of Cerebral Extravasation by Evans Blue and Sodium Fluorescein in Rats. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068595"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e83","DOI":"10.1002\/cpim.83","article-title":"Using Evans Blue Dye to Determine Blood-Brain Barrier Integrity in Rodents","volume":"126","author":"Goldim","year":"2019","journal-title":"Curr. Protoc. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1136\/jnnp-2012-303878","article-title":"1H-MR spectroscopy metabolite levels correlate with executive function in vascular cognitive impairment","volume":"84","author":"Gasparovic","year":"2013","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e0079","DOI":"10.1097\/HC9.0000000000000079","article-title":"Novel magnetic resonance KTRANS measurement of blood-brain barrier permeability correlated with covert HE","volume":"7","author":"Chaganti","year":"2023","journal-title":"Hepatol. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/B978-0-444-53485-9.00005-2","article-title":"Clinical magnetic resonance spectroscopy of the central nervous system","volume":"135","year":"2016","journal-title":"Handb. Clin. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1007\/s11064-015-1581-6","article-title":"The Glymphatic System\u2014A Beginner\u2019s Guide","volume":"40","author":"Jessen","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Dalangin, R., Kim, A., and Campbell, R.E. (2020). The Role of Amino Acids in Neurotransmission and Fluorescent Tools for Their Detection. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176197"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Derbyshire, E., and Obeid, R. (2020). Choline, Neurological Development and Brain Function: A Systematic Review Focusing on the First 1000 Days. Nutrients, 12.","DOI":"10.3390\/nu12061731"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/0-387-30172-0_17","article-title":"N-acetylaspartate as a marker of neuronal injury in neurodegenerative disease","volume":"576","author":"Schuff","year":"2006","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41392-023-01486-5","article-title":"Role of neuroinflammation in neurodegeneration development","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Al-Qahtani, A.A., Alhamlan, F.S., and Al-Qahtani, A.A. (2024). Pro-Inflammatory and Anti-Inflammatory Interleukins in Infectious Diseases: A Comprehensive Review. Trop. Med. Infect. Dis., 9.","DOI":"10.3390\/tropicalmed9010013"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e208016","DOI":"10.1212\/WNL.0000000000208016","article-title":"C-Reactive Protein, Interleukin-6, and Vascular Recurrence According to Stroke Subtype: An Individual Participant Data Meta-Analysis","volume":"102","author":"McCabe","year":"2024","journal-title":"Neurology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.trsl.2020.10.004","article-title":"Inhibition of endogenous blood glutamate oxaloacetate transaminase enhances the ischemic damage","volume":"230","author":"Rabinkov","year":"2021","journal-title":"Transl. 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