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Mitochondrial dysfunction may drive the mechanisms underlying neuronal cell death, thereby making mitochondria prime targets for neuroprotection. The mitochondrial permeability transition pore (mPTP) is one such target within mitochondria. In adult animal models, mPTP inhibition is neuroprotective. However, evidence for mPTP inhibition in neonatal models of neurologic disease is less certain. We tested the therapeutic efficacy of the mPTP small molecule inhibitor GNX\u20104728 and examined the developmental presence of brain mPTP proteins for drug targeting in a neonatal piglet model of hypoxic\u2010ischemic brain injury. Male neonatal piglets were randomized to hypoxia\u2010ischemia (HI) or sham procedure with GNX\u20104728 (15\u00a0mg\/kg, IV) or vehicle (saline\/cyclodextrin\/DMSO, IV). GNX\u20104728 was administered as a single dose within 5\u00a0min after resuscitation from bradycardic arrest. Normal, ischemic, and injured neurons were counted in putamen and somatosensory cortex using hematoxylin and eosin staining. In separate neonatal and juvenile pigs, western blots of putamen mitochondrial\u2010enriched fractions were used to evaluate mitochondrial integrity and the presence of mPTP proteins. We found that a single dose of GNX\u20104728 did not protect putamen and cortical neurons from cell death after HI. However, loss of mitochondrial matrix integrity occurred within 6h after HI, and while mPTP components are present in the neonatal brain their levels were significantly different compared to that of a mature juvenile brain. Thus, the neonatal brain mPTP may not be a good target for current neurotherapeutic drugs that are developed based on adult mitochondria.<\/jats:p>","DOI":"10.1002\/jnr.24821","type":"journal-article","created":{"date-parts":[[2021,3,6]],"date-time":"2021-03-06T01:24:10Z","timestamp":1614993850000},"page":"1550-1564","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Targeting the mitochondrial permeability transition pore for neuroprotection in a piglet model of neonatal hypoxic\u2010ischemic encephalopathy"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2644-1667","authenticated-orcid":false,"given":"May W.","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Neonatology Department of Pediatrics Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polan","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Kulikowicz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond C.","family":"Koehler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8961-7020","authenticated-orcid":false,"given":"Lee J.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Pathology Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000072783.22373.FF"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/biof.5520080315"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.05.002"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1639-11.2011"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-animal-022114-111049"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-3782(79)90022-7"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm500547c"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2019.02.030"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clp.2009.07.011"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70261-8"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.02.021"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(79)90371-0"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003311.pub3"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X18797328"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1159\/000452833"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1159\/000448585"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0b013e31824762d5"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M805235200"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61698-6"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1089\/08977150260190410"},{"key":"e_1_2_12_22_1","first-page":"1","article-title":"Role of mitochondria in neonatal hypoxic\u2010ischemic brain injury","volume":"2","author":"Lu Y.","year":"2015","journal-title":"Journal of Neuroscience and Rehabilitation"},{"key":"e_1_2_12_23_1","first-page":"455","article-title":"Neuronal cell death in nervous system development, disease, and injury (Review)","volume":"7","author":"Martin L. 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