{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T03:27:04Z","timestamp":1792898824876,"version":"4.5.0"},"reference-count":109,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS107417"],"award-info":[{"award-number":["R01 NS107417"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS113921"],"award-info":[{"award-number":["R01 NS113921"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cerebral hypoxia-ischemia (HI) compromises the proteasome in a clinically relevant neonatal piglet model. Protecting and activating proteasomes could be an adjunct therapy to hypothermia. We investigated whether chymotrypsin-like proteasome activity differs regionally and developmentally in the neonatal brain. We also tested whether neonatal brain proteasomes can be modulated by oleuropein, an experimental pleiotropic neuroprotective drug, or by targeting a proteasome subunit gene using recombinant adeno-associated virus-9 (AAV). During post-HI hypothermia, we treated piglets with oleuropein, used AAV-short hairpin RNA (shRNA) to knock down proteasome activator 28\u03b3 (PA28\u03b3), or enforced PA28\u03b3 using AAV-PA28\u03b3 with green fluorescent protein (GFP). Neonatal neocortex and subcortical white matter had greater proteasome activity than did liver and kidney. Neonatal white matter had higher proteasome activity than did juvenile white matter. Lower arterial pH 1 h after HI correlated with greater subsequent cortical proteasome activity. With increasing brain homogenate protein input into the assay, the initial proteasome activity increased only among shams, whereas HI increased total kinetic proteasome activity. OLE increased the initial neocortical proteasome activity after hypothermia. AAV drove GFP expression, and white matter PA28\u03b3 levels correlated with proteasome activity and subunit levels. However, AAV proteasome modulation varied. Thus, neonatal neocortical proteasomes can be pharmacologically activated. HI slows the initial proteasome performance, but then augments ongoing catalytic activity. AAV-mediated genetic manipulation in the piglet brain holds promise, though proteasome gene targeting requires further development.<\/jats:p>","DOI":"10.3390\/cells10082120","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T10:54:35Z","timestamp":1629284075000},"page":"2120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Oleuropein Activates Neonatal Neocortical Proteasomes, but Proteasome Gene Targeting by AAV9 Is Variable in a Clinically Relevant Piglet Model of Brain Hypoxia-Ischemia and Hypothermia"],"prefix":"10.3390","volume":"10","author":[{"given":"Nagat","family":"El Demerdash","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May W.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin E.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Kulikowicz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee J.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, 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, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"key":"ref_1","first-page":"409","article-title":"No cry at birth: Global estimates of intrapartum stillbirths and intrapartum-related neonatal deaths","volume":"83","author":"Lawn","year":"2005","journal-title":"Bull. 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