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Nevertheless, the mechanisms involved are not yet clear. In this context, the aim of this study was to investigate the effects of neonatal HI and environmental stimulation in the hippocampus of rats at 3 different time points (PND 8, 22 and 60), evaluating some aspects of BBB structure and function. Seven\u2010day\u2010old Wistar rats were divided into four groups: a control group maintained in a standard environment (CTSE), a control group maintained in an enrichment environment (CTEE), an HI group maintained in a standard environment (HISE) and an HI group maintained in an enrichment environment (HIEE). At the 7th postnatal day (PND), rats were submitted to the Levine\u2010Rice model of neonatal HI. This method consists of permanent occlusion of the right common carotid artery with subsequent exposure to hypoxia. Rats from CTEE and HIEE were stimulated with environmental enrichment. The EE protocol started 24 h after HI, in which pup rats with their dams were stimulated in a maintained EE (PND 8\u201322). Subsequently, animals were submitted to daily EE (1 h\/day, PND 23\u201360). The expression of some proteins involved in BBB structure (\u03b2\u2010catenin, occludin, connexin\u201043, aquaporin\u20104, glut\u20101 and GFAP) were quantified by western blotting in the hippocampi of rats in three periods, at PND 8, 22 and 60. The BBB permeability and integrity was assessed by Evans blue staining and the immunohistochemistry for GFAP in the CA1 region of the hippocampus were also performed. The results showed an HI\u2010induced decreased occludin expression at PND 22 and low levels of occludin, \u03b2\u2010catenin and GFAP at PND 60 in the hippocampus of the hypoxic\u2010ischemic rats. Interestingly, in young and adult rats, EE reversed these effects. Evans blue extravasation into the brain parenchyma confirmed the BBB dysfunction brought on by HI. No differences were observed at PND 8, probably due to the immaturity of the BBB at this age. The present study makes an important contribution to understanding the mechanism of the hypoxic\u2010ischemic brain damage and also to presents, for the first time, the recovery of BBB dysfunction as a possible pathway for the protective effect of EE.<\/jats:p>","DOI":"10.1016\/j.ijdevneu.2016.06.006","type":"journal-article","created":{"date-parts":[[2016,6,22]],"date-time":"2016-06-22T18:56:32Z","timestamp":1466621792000},"page":"35-45","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Environmental enrichment attenuates the blood brain barrier dysfunction induced by the neonatal hypoxia\u2010ischemia"],"prefix":"10.1002","volume":"53","author":[{"given":"Ramiro","family":"Diaz","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Neuroci\u00eancias Universidade Federal do Rio Grande do Sul Porto Alegre RS Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia Maidana","family":"Miguel","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Neuroci\u00eancias Universidade Federal do Rio Grande do Sul Porto Alegre RS Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna Ferrary","family":"Deniz","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Neuroci\u00eancias Universidade Federal do Rio Grande do Sul Porto Alegre RS Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helo\u00edsa Deola","family":"Confortim","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Neuroci\u00eancias Universidade Federal do Rio Grande do Sul Porto Alegre RS Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00edlvia","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Neuroci\u00eancias Universidade Federal do Rio Grande do Sul Porto Alegre RS Brazil"},{"name":"Departamento de Ci\u00eancias Morfol\u00f3gicas Universidade Federal do Rio Grande do Sul Porto Alegre RS Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique Culturato Padilha","family":"Mendon\u00e7a","sequence":"additional","affiliation":[{"name":"Departamento de Farmacologia, Faculdade de Ci\u00eancias M\u00e9dicas Universidade Estadual de Campinas (UNICAMP) Campinas SP Brazil"},{"name":"Departamento de Bioqu\u00edmica e Biologia Tecidual Instituto de Biologia (IB), Universidade Estadual de Campinas (UNICAMP) Campinas SP Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Alice","family":"da Cruz\u2010H\u00f6fling","sequence":"additional","affiliation":[{"name":"Departamento de Farmacologia, Faculdade de Ci\u00eancias M\u00e9dicas Universidade Estadual de Campinas (UNICAMP) Campinas SP Brazil"},{"name":"Departamento de Bioqu\u00edmica e Biologia Tecidual Instituto de Biologia (IB), Universidade Estadual de Campinas (UNICAMP) Campinas SP Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenir Orlandi","family":"Pereira","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Neuroci\u00eancias Universidade Federal do Rio Grande do Sul Porto Alegre RS Brazil"},{"name":"Departamento de Ci\u00eancias Morfol\u00f3gicas Universidade Federal do Rio Grande do Sul Porto Alegre RS Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,6,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1824"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.07.030"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-013-9608-0"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000103741"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnsys.2014.00156","article-title":"Environmental enrichment and the sensory brain: the role of enrichment in remediating brain injury","volume":"8","author":"Alwis D.S.","year":"2014","journal-title":"Front. 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