{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T02:03:05Z","timestamp":1771639385204,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2014,4,4]],"date-time":"2014-04-04T00:00:00Z","timestamp":1396569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cathepsin B is one of the major lysosomal cysteine proteases involved in neuronal protein catabolism. This cathepsin is released after traumatic injury and increases neuronal death; however, release of cystatin C, a cathepsin inhibitor, appears to be a  self-protective brain response. Here we describe the effect of cystatin C intracerebroventricular administration in rats prior to inducing a traumatic brain injury. We observed that cystatin C injection caused a dual response in post-traumatic brain injury recovery: higher doses (350 fmoles) increased bleeding and mortality, whereas lower doses (3.5 to 35 fmoles) decreased bleeding, neuronal damage and mortality. We also analyzed the expression of cathepsin B and cystatin C in the brains of control rats and of rats after a traumatic brain injury. Cathepsin B was detected in the brain stem, cerebellum, hippocampus and cerebral cortex of control rats. Cystatin C was localized to the choroid plexus, brain stem and cerebellum of control rats. Twenty-four hours after traumatic brain injury, we observed changes in both the expression and localization of both proteins in the cerebral cortex, hippocampus and brain stem. An early increase and intralysosomal expression of cystatin C after brain injury was associated with reduced neuronal damage.<\/jats:p>","DOI":"10.3390\/ijms15045807","type":"journal-article","created":{"date-parts":[[2014,4,4]],"date-time":"2014-04-04T11:11:12Z","timestamp":1396609872000},"page":"5807-5820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Cystatin C Has a Dual Role in Post-Traumatic Brain  Injury Recovery"],"prefix":"10.3390","volume":"15","author":[{"given":"Marina","family":"Martinez-Vargas","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Medicine, Universidad Nacional Autonoma de Mexico,  Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maribel","family":"Soto-Nu\u00f1ez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Universidad Nacional Autonoma de Mexico, Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Tabla-Ramon","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Universidad Nacional Autonoma de Mexico,  Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Solis","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Universidad Nacional Autonoma de Mexico,  Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben","family":"Gonzalez-Rivera","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Universidad Nacional Autonoma de Mexico,  Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adan","family":"Perez-Arredondo","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Universidad Nacional Autonoma de Mexico,  Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Estrada-Rojo","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Universidad Nacional Autonoma de Mexico,  Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andres","family":"Castell","sequence":"additional","affiliation":[{"name":"Department of Cell and Tissue Biology, School of Medicine Universidad Nacional Autonoma de Mexico, Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Molina-Guarneros","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Universidad Nacional Autonoma de Mexico, Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luz","family":"Navarro","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Universidad Nacional Autonoma de Mexico,  Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/S1474-4422(08)70164-9","article-title":"Moderate and severe traumatic injury in adults","volume":"7","author":"Maas","year":"2008","journal-title":"Lancet Neurol"},{"key":"ref_2","unstructured":"Faul, M.D., Xu, L., Wald, M.M., and Coronado, V.G. Available online: http:\/\/www.cdc.gov\/traumaticbraininjury\/pdf\/blue_book.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0165-0173(02)00157-1","article-title":"Cerebral ischemia and trauma different etiologies yet similar mechanisms: Neuroprotective opportunities","volume":"39","author":"Leker","year":"2002","journal-title":"Brain Res. Rev"},{"key":"ref_4","first-page":"541","article-title":"Protective mechanisms by cystatin C in neurodegenerative diseases","volume":"3","author":"Gauthier","year":"2012","journal-title":"Front. Biosci. (Schol. Ed.)"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1038\/sj.onc.1207512","article-title":"Lysosomes in cell death","volume":"23","author":"Guicciardi","year":"2004","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s10495-006-3486-y","article-title":"Cathepsin-regulated apoptosis","volume":"11","author":"Chwieralski","year":"2006","journal-title":"Apoptosis"},{"key":"ref_7","first-page":"410","article-title":"Expression of cathepsin-B and -D in rat\u2019s brain after traumatic brain injury","volume":"22","author":"Zhang","year":"2006","journal-title":"Fa Yi Xue Za Zhi"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1089\/neu.2013.2944","article-title":"The cysteine protease cathepsin B is a key drug target and cysteine protease inhibitors are potential therapeutics for traumatic brain injury","volume":"31","author":"Hook","year":"2014","journal-title":"J. Neurotrauma"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1002\/jnr.22453","article-title":"Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway","volume":"88","author":"Luo","year":"2010","journal-title":"J. Neurosci. Res"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.cbi.2006.04.013","article-title":"The lysosomal-mitochondrial axis theory of postmitotic aging and cell death","volume":"163","author":"Terman","year":"2006","journal-title":"Chem. Biol. Interact"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.neulet.2006.02.010","article-title":"Recovery after a traumatic brain injury depends on diurnal variations. Effect of cystatin C","volume":"400","author":"Navarro","year":"2006","journal-title":"Neurosci. Lett"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11282","DOI":"10.1016\/S0021-9258(18)67380-6","article-title":"Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids","volume":"261","author":"Abrahamson","year":"1986","journal-title":"J. Biol. Chem"},{"key":"ref_13","first-page":"WMC003319","article-title":"Cystatin C decreases the body temperature and pain perception","volume":"3","author":"Navarro","year":"2012","journal-title":"WebmedCentral PAIN"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"M156","DOI":"10.12968\/hmed.2009.70.Sup10.44641","article-title":"Understanding the metabolic response to trauma","volume":"70","author":"Sritharan","year":"2009","journal-title":"Br. J. Hosp. Med. (Lond.)"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0006-8993(03)03525-X","article-title":"Neuroprotective effects of insulin-like growth factor-I (IGF-I) following a penetrating brain injury in rats","volume":"991","author":"Kazanis","year":"2003","journal-title":"Brain Res"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0301-0082(00)00006-X","article-title":"Implication of cysteine protease calpain, cathepsin and caspase in ischemic neuronal death of primates","volume":"62","author":"Yamashima","year":"2000","journal-title":"Prog. Neurobiol"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1749-6632.2002.tb04832.x","article-title":"Cystatin C induces neuronal cell death in vivo","volume":"977","author":"Nagai","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.brainres.2005.10.063","article-title":"Neuronal cell death induced by cystatin C in vivo and in cultured human CNS neurons is inhibited with cathepsin B","volume":"1066","author":"Nagai","year":"2005","journal-title":"Brain Res"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.neuroscience.2004.06.024","article-title":"Gene deletion of cystatin C aggravates brain damage following focal ischemia but mitigates the neuronal injury after global ischemia in the mouse","volume":"128","author":"Olson","year":"2004","journal-title":"Neuroscience"},{"key":"ref_20","first-page":"313","article-title":"Cathepsin B immunoreactive neurons in rat brain. A combined light and electron microscopic study","volume":"30","author":"Bernstein","year":"1989","journal-title":"J. Hirnforsch"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0006-8993(99)01888-0","article-title":"Age-related changes in ultrastructural features of cathepsin B- and d-containing neurons in rat cerebral cortex","volume":"844","author":"Jung","year":"1999","journal-title":"Brain Res"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/0306-4522(94)90190-2","article-title":"Differential distribution of messenger RNAs for cathepsins B, L and S in adult rat brain: An in situ hybridization study","volume":"59","author":"Petanceska","year":"1994","journal-title":"Neuroscience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/S0002-9440(10)61781-6","article-title":"Elevation of cystatin C in susceptible neurons in Alzheimer\u2019s disease","volume":"159","author":"Deng","year":"2001","journal-title":"Am. J. Pathol"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1007\/s004010050644","article-title":"Cystatin C and transthyretin expression in normal and neoplastic tissues of thehuman brain and pituitary","volume":"93","author":"Lignelid","year":"1997","journal-title":"Acta Neuropathol"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/0006-8993(93)90941-F","article-title":"Expression of cystatin C in rat, monkey and human brains","volume":"628","author":"Yasuhara","year":"1993","journal-title":"Brain Res"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"716","DOI":"10.3171\/jns.1997.87.5.0716","article-title":"Cathepsin B and middle cerebral artery occlusion in the rat","volume":"87","author":"Seyfried","year":"1997","journal-title":"J. Neurosurg"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1007\/s11064-007-9567-7","article-title":"Activation of calpain, cathepsin-b and caspase-3 during transient focal cerebral ischemia in rat model","volume":"33","author":"Chaitanya","year":"2008","journal-title":"Neurochem. Res"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/S0006-8993(96)01403-5","article-title":"A comparison of cathepsin B processing and distribution during neuronal death in rats following global ischemia or decapitation necrosis","volume":"751","author":"Hill","year":"1997","journal-title":"Brain Res"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1006\/bbrc.1996.1706","article-title":"Dynamic changes of cathepsins B and L expression in the monkey hippocampus after transient ischemia","volume":"228","author":"Kohda","year":"1996","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1046\/j.1460-9568.1998.00184.x","article-title":"Inhibition of ischaemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: A novel strategy for neuroprotection based on \u201ccalpain-cathepsin hypothesis\u201d","volume":"10","author":"Yamashima","year":"1998","journal-title":"Eur. J. Neurosci"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0006-8993(95)00520-Z","article-title":"Cystatin C, a protease inhibitor, in degenerating rat hippocampal neurons following transient forebrain ischemia","volume":"691","author":"Palm","year":"1995","journal-title":"Brain Res"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0006-8993(95)01232-X","article-title":"Cystatin C and apolipoprotein E immunoreactivities in CA1 neurons in ischemic gerbil hippocampus","volume":"709","author":"Ishimaru","year":"1996","journal-title":"Brain Res"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.neulet.2005.10.091","article-title":"Cystatin C expression is increased in the hippocampus following photothrombotic stroke in rat","volume":"395","year":"2006","journal-title":"Neurosci. Lett"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/978-1-4613-0335-0_22","article-title":"Participation of cathepsins B, H, and L in perikaryal condensation of CA1 pyramidal neurons undergoing apoptosis after brief ischemia","volume":"389","author":"Nitatori","year":"1996","journal-title":"Adv. Exp. Med. Biol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.nbd.2005.03.006","article-title":"Cystatin C modulates neurodegeneration and neurogenesis following status epilepticus in mouse","volume":"20","author":"Lukasiuk","year":"2005","journal-title":"Neurobiol. Dis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.brainres.2010.09.035","article-title":"Alterations of NMDA receptor subunits NR1, NR2A and NR2B mRNA expression and their relationship to apoptosis following transient forebrain ischemia","volume":"1361","author":"Liu","year":"2010","journal-title":"Brain Res"},{"key":"ref_37","unstructured":"Paxinos, G., and Watson, C. (1998). The Rat Brain in Stereotaxic Coordinates, Academic Press. [4th ed.]."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/S0028-3908(99)00262-2","article-title":"Functional assessments in mice and rats after focal stroke","volume":"39","author":"Hunter","year":"2000","journal-title":"Neuropharmacology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/4\/5807\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:09:57Z","timestamp":1760216997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/4\/5807"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,4]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2014,4]]}},"alternative-id":["ijms15045807"],"URL":"https:\/\/doi.org\/10.3390\/ijms15045807","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,4]]}}}