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Caffeine, which is a competitive inhibitor of adenosine receptors, is commonly used as treatment for preterm apnoea in clinical settings. In the current study, we investigated the effects of caffeine given at 0\u00a0h, 6\u00a0h, 12\u00a0h or 24\u00a0h after HI in P10 mouse pups. Open field and rotarod behavioural tests were performed 2\u00a0weeks after injury, and brain morphology was then evaluated. Gene expression and immunohistological analyses were assessed in mice 1- and 5-day post-HI. A single dose of caffeine directly after HI resulted in a reduction of the lesion in the grey and white matter, judged by immunostaining of MAP2 and MBP, respectively, compared to PBS-treated controls. In addition, the number of amoeboid microglia and apoptotic cells, the area covered by astrogliosis, and the expression of pro-inflammatory cytokines were significantly decreased. Behavioural assessment after 2\u00a0weeks showed increased open-field activity after HI, and this was normalised if caffeine was administered immediately after the injury. Later administrations of caffeine did not change the outcomes when compared to the vehicle group. In conclusion, caffeine only yielded neuroprotection and immunomodulation in a neonatal model of brain hypoxia ischaemia if administered immediately after injury.<\/jats:p>","DOI":"10.1007\/s12035-020-01867-9","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T16:02:31Z","timestamp":1579795351000},"page":"2194-2205","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Defining a Time Window for Neuroprotection and Glia Modulation by Caffeine After Neonatal Hypoxia-Ischaemia"],"prefix":"10.1007","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7853-0912","authenticated-orcid":false,"given":"Elena","family":"Di Martino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Bocchetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunichiro","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeo","family":"Mukai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klas","family":"Blomgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrika","family":"\u00c5d\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,23]]},"reference":[{"issue":"10032","key":"1867_CR1","doi-asserted-by":"publisher","first-page":"2049","DOI":"10.1016\/S0140-6736(15)00519-X","volume":"387","author":"CG Victora","year":"2016","unstructured":"Victora CG, Requejo JH, Barros AJ, Berman P, Bhutta Z, Boerma T, Chopra M, De Francisco A et al (2016) Countdown to 2015: a decade of tracking progress for maternal, newborn, and child survival. 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