{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T12:31:15Z","timestamp":1778589075193,"version":"3.51.4"},"reference-count":37,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["10CVD010"],"award-info":[{"award-number":["10CVD010"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"name":"International Alzheimer's Association","award":["NIRG-305325"],"award-info":[{"award-number":["NIRG-305325"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG062475"],"award-info":[{"award-number":["R01AG062475"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Recent studies of cerebral hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)\u03b21 is highly elevated following HI and that delivering an antagonist for TGF\u03b2 receptor activin-like kinase 5 (ALK5)\u2014SB505124\u2014three days after injury in a rat model of moderate pre-term HI significantly preserved the structural integrity of the thalamus and hippocampus as well as neurological functions associated with those brain structures. To elucidate the mechanism whereby ALK5 inhibition reduces cell death, we assessed levels of autophagy markers in neurons and found that SB505124 increased numbers of autophagosomes and levels of lipidated light chain 3 (LC3), a key protein known to mediate autophagy. However, those studies did not determine whether (1) SB was acting directly on the CNS and (2) whether directly inducing autophagy could decrease cell death and improve outcome. Here we show that administering an ALK5 antagonist three days after HI reduced actively apoptotic cells by ~90% when assessed one week after injury. Ex vivo studies using the lysosomal inhibitor chloroquine confirmed that SB505124 enhanced autophagy flux in the injured hemisphere, with a significant accumulation of the autophagic proteins LC3 and p62 in SB505124 + chloroquine treated brain slices. We independently activated autophagy using the stimulatory peptide Tat-Beclin1 to determine if enhanced autophagy is directly responsible for improved outcomes. Administering Tat-Beclin1 starting three days after injury preserved the structural integrity of the hippocampus and thalamus with improved sensorimotor function. These data support the conclusion that intervening at this phase of injury represents a window of opportunity where stimulating autophagy is beneficial.<\/jats:p>","DOI":"10.3390\/cells10040898","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T15:30:39Z","timestamp":1618414239000},"page":"898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Moderately Inducing Autophagy Reduces Tertiary Brain Injury after Perinatal Hypoxia-Ischemia"],"prefix":"10.3390","volume":"10","author":[{"given":"Brian H.","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Physiology and Neuroscience, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej","family":"Jeziorek","sequence":"additional","affiliation":[{"name":"Federated Department of Biological Sciences, New Jersey Institute of Technology, Rutgers University, Newark, NJ 07102, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6863-3651","authenticated-orcid":false,"given":"Hur Dolunay","family":"Kanal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology and Neuroscience, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1978-4055","authenticated-orcid":false,"given":"Viorica Raluca","family":"Contu","sequence":"additional","affiliation":[{"name":"Federated Department of Biological Sciences, New Jersey Institute of Technology, Rutgers University, Newark, NJ 07102, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1805-5806","authenticated-orcid":false,"given":"Radek","family":"Dobrowolski","sequence":"additional","affiliation":[{"name":"Federated Department of Biological Sciences, New Jersey Institute of Technology, Rutgers University, Newark, NJ 07102, USA"},{"name":"Glenn Biggs Institute for Alzheimer\u2019s &amp; Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven W.","family":"Levison","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology and Neuroscience, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1161\/CIRCULATIONAHA.108.191259","article-title":"Heart disease and stroke statistics\u20142009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee","volume":"119","author":"Adams","year":"2009","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1056\/NEJMra041996","article-title":"Neonatal brain injury","volume":"351","author":"Ferriero","year":"2004","journal-title":"N. 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