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We investigated the regulatory mechanism by which the pre-apoptotic proteins translocate from mitochondria to the cytosol during HI through the Src kinase. Newborn piglets were divided into 3 groups (n\u2009=\u20095\/group): normoxic (Nx), HI and HI pre-treated with Src kinase inhibitor PP2 (PP2\u2009+\u2009HI). Brain tissue HI was verified by neuropathological analysis and by Adenosine Triphosphate (ATP) and Phosphocreatine (PCr) levels. We used western blots, immunohistochemistry, H&amp;E and biochemical enzyme assays to determine the role of Src kinase on mitochondrial membrane apoptotic protein trafficking. HI resulted in decreased ATP and PCr levels, neuropathological changes and increased levels of cytochrome c, Smac\/DIABLO and AIF in the cytosol while their levels were decreased in mitochondria compared to Nx. PP2 decreased the cytosolic levels of pre-apoptotic proteins, attenuated the neuropathological changes and apoptosis and decreased the HI-induced increased activity of caspase-3. Our data suggest that Src kinase may represent a potential target that could interrupt the enzymatic activation of the caspase dependent cell death pathway.<\/jats:p>","DOI":"10.1038\/s41598-017-16983-1","type":"journal-article","created":{"date-parts":[[2017,11,24]],"date-time":"2017-11-24T12:52:31Z","timestamp":1511527951000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Effect of Src Kinase inhibition on Cytochrome c, Smac\/DIABLO and Apoptosis Inducing Factor (AIF) Following Cerebral Hypoxia-Ischemia in Newborn Piglets"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7368-0436","authenticated-orcid":false,"given":"Panagiotis","family":"Kratimenos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Koutroulis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beamon","family":"Agarwal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stamatios","family":"Theocharis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Delivoria-Papadopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,11,30]]},"reference":[{"key":"16983_CR1","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.neulet.2008.05.095","volume":"440","author":"YM Vibert","year":"2008","unstructured":"Vibert, Y. M., Ashraf, Q. M., Mishra, O. P. & Delivoria-Papadopoulos, M. Mechanism of Ca2+\u2212influx and Ca2+\/calmodulin-dependent protein kinase IV activity during in utero HI in cerebral cortical neuronal nuclei of the guinea pig fetus at term. Neurosci Lett \n                           440, 227\u2013231, https:\/\/doi.org\/10.1016\/j.neulet.2008.05.095 (2008).","journal-title":"Neurosci Lett"},{"key":"16983_CR2","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1023\/A:1020950019986","volume":"24","author":"SA Zanelli","year":"1999","unstructured":"Zanelli, S. A., Numagami, Y., McGowan, J. E., Mishra, O. P. & Delivoria-Papadopoulos, M. NMDA receptor-mediated calcium influx in cerebral cortical synaptosomes of the hypoxic guinea pig fetus. Neurochem Res \n                           24, 437\u2013446 (1999).","journal-title":"Neurochem Res"},{"key":"16983_CR3","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1159\/000064152","volume":"82","author":"KI Fritz","year":"2002","unstructured":"Fritz, K. I., Zubrow, A. B., Mishra, O. P. & Delivoria-Papadopoulos, M. NMDA receptor modification during graded HI in the cerebral cortex of newborn piglets. Biol Neonate \n                           82, 46\u201352 (2002).","journal-title":"Biol Neonate"},{"key":"16983_CR4","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1007\/BF00968404","volume":"17","author":"OP Mishra","year":"1992","unstructured":"Mishra, O. P. & Delivoria-Papadopoulos, M. Modification of modulatory sites of NMDA receptor in the fetal guinea pig brain during development. 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Nuclear mechanisms of hypoxic cerebral injury in the newborn: the role of caspases. Semin Perinatol \n                           32, 334\u2013343, https:\/\/doi.org\/10.1053\/j.semperi.2008.07.002 (2008).","journal-title":"Semin Perinatol"},{"key":"16983_CR7","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1517\/14728222.2014.952280","volume":"18","author":"P Kratimenos","year":"2014","unstructured":"Kratimenos, P. et al. Multi-targeted molecular therapeutic approach in aggressive neuroblastoma: the effect of Focal Adhesion Kinase-Src-Paxillin system. Expert Opin Ther Targets \n                           18, 1395\u20131406, https:\/\/doi.org\/10.1517\/14728222.2014.952280 (2014).","journal-title":"Expert Opin Ther Targets"},{"key":"16983_CR8","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1038\/nature03469","volume":"434","author":"Y Wang","year":"2005","unstructured":"Wang, Y. et al. Visualizing the mechanical activation of Src. 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