{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:02:35Z","timestamp":1760234555093,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["2015-257390-M","630838"],"award-info":[{"award-number":["2015-257390-M","630838"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tuberculosis (TB) is an important infectious disease and a public health problem. The organs most frequently affected by TB are the lungs; despite this, it has been reported that TB patients suffer from depression and anxiety, which have been attributed to social factors. In previous experimental work, we observed that the extensive pulmonary inflammation characteristic of TB with high cytokine production induces neuroinflammation, neuronal death and behavioral abnormalities in the absence of brain infection. The objective of the present work was to reduce this neuroinflammation and avoid the psycho-affective disorders showed during pulmonary TB. Glucocorticoids (GCs) are the first-line treatment for neuroinflammation; however, their systemic administration generates various side effects, mostly aggravating pulmonary TB due to immunosuppression of cellular immunity. Intranasal administration is a route that allows drugs to be released directly in the brain through the olfactory nerve, reducing their doses and side effects. In the present work, dexamethasone\u2019s (DEX) intranasal administration was evaluated in TB BALB \/c mice comparing three different doses (0.05, 0.25 and 2.5 mg\/kg BW) on lung disease evolution, neuroinflammation and behavioral alterations. Low doses of dexamethasone significantly decreased neuroinflammation, improving behavioral status without aggravating lung disease.<\/jats:p>","DOI":"10.3390\/ijms22115997","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T15:58:44Z","timestamp":1622563124000},"page":"5997","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Therapeutic Effect of Intranasal Administration of Dexamethasone in Neuroinflammation Induced by Experimental Pulmonary Tuberculosis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6635-2939","authenticated-orcid":false,"given":"Jacqueline V.","family":"Lara-Espinosa","sequence":"first","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Fernanda","family":"Arce-Aceves","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dulce","family":"Mata-Espinosa","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Barrios-Pay\u00e1n","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brenda","family":"Marquina-Castillo","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rogelio","family":"Hern\u00e1ndez-Pando","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory responses and inflammation-associated diseases in organs","volume":"9","author":"Chen","year":"2018","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/cshperspect.a001651","article-title":"The nuclear factor NF-kappaB pathway in inflammation","volume":"1","author":"Lawrence","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/nyas.13985","article-title":"Sepsis: Developing new alternatives to reduce neuroinflammation and attenuate brain injury","volume":"1437","author":"Meneses","year":"2019","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.1600-065X.2006.00441.x","article-title":"CNS immune privilege: Hiding in plain sight","volume":"213","author":"Carson","year":"2006","journal-title":"Immunol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8071","DOI":"10.1007\/s12035-016-0297-1","article-title":"Inflammatory Response in the CNS: Friend or Foe?","volume":"54","author":"Sochocka","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1080\/00207454.2016.1212854","article-title":"Neuroinflammation pathways: A general review","volume":"127","author":"Shabab","year":"2017","journal-title":"Int. J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ni.3656","article-title":"Infectious immunity in the central nervous system and brain function","volume":"18","author":"Klein","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_8","first-page":"1","article-title":"Neu-roinflammation Induces Neurodegeneration","volume":"1","author":"Kempuraj","year":"2016","journal-title":"J. Neurol. Neurosurg Spine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10018","DOI":"10.1002\/jcp.27860","article-title":"Strategies toward rheumatoid arthritis therapy; the old and the new","volume":"234","author":"Abbasi","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4805","DOI":"10.1096\/fj.12-216382","article-title":"Mechanisms of the anti-inflammatory effects of glucocorticoids: Genomic and nongenomic interference with MAPK signaling pathways","volume":"26","author":"Ayroldi","year":"2012","journal-title":"FASEB J."},{"key":"ref_11","first-page":"20","article-title":"One hormone, two actions: Anti- And pro-inflammatory effects of glucocorticoids","volume":"22","author":"Cidlowski","year":"2014","journal-title":"Neuroim-munomodulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1007\/s00401-007-0195-8","article-title":"Dexamethasone attenuates early expression of three molecules associated with microglia\/macrophages activation following rat traumatic brain injury","volume":"113","author":"Zhang","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1080\/10408360590888983","article-title":"Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis","volume":"42","author":"Tuckermann","year":"2005","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1007\/s13311-020-00884-9","article-title":"Intranasal Dexamethasone Reduces Mortality and Brain Damage in a Mouse Experimental Is-chemic Stroke Model","volume":"17","author":"Espinosa","year":"2020","journal-title":"Neurotherapeutics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1080\/14656566.2020.1807514","article-title":"Advances with glucocorticoids in the treatment of asthma: State of the art","volume":"21","author":"Ora","year":"2020","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/j.rmed.2005.11.020","article-title":"Systemic side effects of inhaled corticosteroids in patients with asthma","volume":"100","author":"Dahl","year":"2006","journal-title":"Respir. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/cei.13018","article-title":"Intranasal delivery of dexamethasone efficiently controls LPS-induced murine neuroinflammation","volume":"190","author":"Meneses","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"709","DOI":"10.4155\/tde.14.41","article-title":"The nasal approach to delivering treatment for brain diseases: An anatomic, physiologic, and delivery technology overview","volume":"5","author":"Djupesland","year":"2014","journal-title":"Ther. Deliv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16076","DOI":"10.1038\/nrdp.2016.76","article-title":"Tuberculosis","volume":"2","author":"Pai","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.ccm.2019.07.009","article-title":"The Future of Vaccines for Tuberculosis","volume":"40","author":"Stockdale","year":"2019","journal-title":"Clin. Chest Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"930","DOI":"10.3389\/fimmu.2020.00930","article-title":"Evidence for the Effect of Vaccination on Host-Pathogen Interactions in a Murine Model of Pulmonary Tuberculosis by Mycobacterium tuberculosis","volume":"11","author":"Anthony","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"31","DOI":"10.4236\/jtr.2021.91003","article-title":"Psychiatric Problems in Pulmonary Tuberculosis: Depression and Anxiety","volume":"9","year":"2021","journal-title":"J Tuberc Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e505","DOI":"10.4088\/JCP.14m09403","article-title":"Association of pulmonary tuberculosis and ethambutol with incident depressive disorder: A nationwide, population-based cohort study","volume":"76","author":"Yen","year":"2015","journal-title":"J. Clin. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4172\/2167-1044.1000253","article-title":"Depression and its Associated Factors with Multidrug-Resistant Tuberculosis at Baseline","volume":"6","author":"Javaid","year":"2017","journal-title":"J. Depress. Anxiety"},{"key":"ref_25","first-page":"66","article-title":"Psychiatric morbidity in pulmonary tuberculosis\u2014A clinical study","volume":"23","author":"Mathai","year":"1981","journal-title":"Indian J. Psychiatry"},{"key":"ref_26","first-page":"18","article-title":"Depression: A neglected comorbidity in patients with tuberculosis","volume":"66","author":"Shyamala","year":"2018","journal-title":"J. Assoc. Physicians India"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1159\/000097202","article-title":"Passage of Cytokines across the Blood-Brain Barrier","volume":"2","author":"Banks","year":"1995","journal-title":"Neuroimmunomodulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E163","DOI":"10.1152\/ajpendo.1990.258.1.E163","article-title":"Involvement of organum vasculosum of lamina terminalis and preoptic area in interleukin 1\u03b2-induced ACTH release","volume":"258","author":"Katsuura","year":"1990","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/0024-3205(95)02047-M","article-title":"Cytokine-to-brain communication: A review & analysis of alternative mechanisms","volume":"57","author":"Watkins","year":"1995","journal-title":"Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1017\/S1461145709009924","article-title":"A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder","volume":"12","author":"Khairova","year":"2009","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.ncl.2006.03.003","article-title":"Cytokine, Sickness Behavior, and Depression","volume":"24","author":"Dantzer","year":"2006","journal-title":"Neurol. Clin."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1111\/cei.13351","article-title":"From early adversities to immune activation in psychiatric disorders: The role of the sympathetic nervous system","volume":"197","author":"Mondelli","year":"2019","journal-title":"Clin. Exp. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lara-Espinosa, J.V., Santana-Mart\u00ednez, R.A., Maldonado, P.D., Zetter, M., Becerril-Villanueva, E., P\u00e9rez-S\u00e1nchez, G., Pav\u00f3n, L., Mata-Espinosa, D., Barrios-Pay\u00e1n, J., and L\u00f3pez-Torres, M.O. (2020). Experimental pulmonary tuberculosis in the absence of detectable brain infection induces neuroinflammation and behavioural abnormalities in male balb\/c mice. Int. J. Mol. Sci., 21.","DOI":"10.21203\/rs.3.rs-24798\/v1"},{"key":"ref_34","first-page":"214","article-title":"Behavioral and biochemical characterisation of elevated \u201cI-maze\u201d as animal model of anxiety","volume":"4","author":"Gilhotra","year":"2015","journal-title":"Beni-Suef Univ. J. Basic Appl. Sci."},{"key":"ref_35","first-page":"1","article-title":"Drug delivery systems, CNS protection, and the blood brain barrier","volume":"2014","author":"Upadhyay","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1093\/jnen\/nlz128","article-title":"Intranasal methylprednisolone effectively reduces neuroinflammation in mice with experimental auto-immune encephalitis","volume":"79","author":"Rassy","year":"2020","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/pr.2012.9","article-title":"Dexamethasone and betamethasone protect against lip-opolysaccharide-induced brain damage in neonatal rats","volume":"71","author":"Pang","year":"2012","journal-title":"Pediatr. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1097\/CCM.0b013e31820edf75","article-title":"Mild versus strong anti-inflammatory therapy during early sepsis in mice: A matter of life and death","volume":"39","author":"Bastiaans","year":"2011","journal-title":"Crit. Care Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.tem.2012.11.005","article-title":"The five Rs of glucocorticoid action during inflammation: Ready, reinforce, repress, resolve, and restore","volume":"24","author":"Busillo","year":"2013","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.mce.2007.04.014","article-title":"Glucocorticoids and the innate immune system: Crosstalk with the Toll-like receptor signaling network","volume":"275","author":"Chinenov","year":"2007","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"38703","DOI":"10.1074\/jbc.M111.275370","article-title":"Glucocorticoids sensitise the innate immune system through regulation of the NLRP3 inflammasome","volume":"286","author":"Busillo","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1124\/jpet.110.171975","article-title":"Dexamethasone enhances ATP-induced inflammatory responses in en-dothelial cells","volume":"335","author":"Ding","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_43","first-page":"38","article-title":"Concentration Dependent Actions of Glucocorticoids on Neuronal Viability and Sur-vival","volume":"4","author":"Meerlo","year":"2006","journal-title":"Dose-Response"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1590\/S0100-879X2006001100002","article-title":"Immune factors and immunoregulation in tuberculosis","volume":"39","author":"Ferraz","year":"2006","journal-title":"Brazilian, J. Med. Biol. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1007\/BF01420304","article-title":"Dexamethasone and colchicine reduce inflammation and delayed oedema following experimental brain contusion","volume":"138","author":"Holmin","year":"1996","journal-title":"Acta Neurochir."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"35002","DOI":"10.1088\/1748-605X\/abc7f1","article-title":"Hydrogel-mediated local delivery of dexamethasone reduces neuroinflammation after traumatic brain injury","volume":"16","author":"Jeong","year":"2021","journal-title":"Biomed. Mater."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1530\/JOE-13-0022","article-title":"Combination therapy with melatonin and dexamethasone in a mouse model of traumatic brain injury","volume":"217","author":"Campolo","year":"2013","journal-title":"J. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.anai.2016.06.009","article-title":"Safety of intranasal corticosteroids","volume":"117","author":"Bensch","year":"2016","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_49","first-page":"2637","article-title":"Dexamethasone for the Treatment of Coronavirus Disease (COVID-19): A Review. SN Compr","volume":"2","author":"Ahmed","year":"2020","journal-title":"Clin. Med."},{"key":"ref_50","first-page":"26","article-title":"Correlation between the kinetics of Th1, Th2 cells and pathology in a murine model of experimental pulmonary tuberculosis","volume":"89","author":"Orozcoe","year":"1996","journal-title":"Immunology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.tube.2010.05.002","article-title":"Specific bacterial genotypes of Mycobacterium tuberculosis cause extensive dissemination and brain infection in an experimental model","volume":"90","author":"Aguilar","year":"2010","journal-title":"Tuberculosis"},{"key":"ref_52","unstructured":"Franklin, K.B.J., and Paxinos, G. (2013). Paxinos and Franklin\u2019s the Mouse Brain in Stereotaxic Coordinates, Elsevier."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analysing real-time PCR data by the comparative CT method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1038\/nn.2647","article-title":"Animal models of neuropsychiatric disorders","volume":"13","author":"Nestler","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1097\/00004647-200002000-00019","article-title":"Experimental closed head injury: Analysis of neurological outcome, blood-brain barrier dysfunction, in-tracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines","volume":"20","author":"Stahel","year":"2000","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/PL00005603","article-title":"Spontaneous object recognition and object location memory in rats: The effects of lesions in the cingulate cortices, the medial prefrontal cortex, the cingulum bundle and the fornix","volume":"113","author":"Ennaceur","year":"1997","journal-title":"Exp. Brain Res."},{"key":"ref_57","unstructured":"(2021, May 20). GraphPad Software; Version 9.1.1.225; Software for Biostatistics. Available online: https:\/\/crackproduct.com\/graphpad-prism\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5997\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:57Z","timestamp":1760162997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5997"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,1]]},"references-count":57,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115997"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115997","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,6,1]]}}}