{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:33:07Z","timestamp":1761060787369,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,4,26]],"date-time":"2019-04-26T00:00:00Z","timestamp":1556236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["NS099628"],"award-info":[{"award-number":["NS099628"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neonatal hypoxia\u2013ischemia (HI) is a major cause of death and disability in neonates. HI leads to a dramatic rise in intracellular calcium levels, which was originally thought to be detrimental to the brain. However, it has been increasingly recognized that this calcium signaling may also play an important protective role after injury by triggering endogenous neuroprotective pathways. Calcium\/calmodulin-dependent protein kinase kinase \u03b2 (CaMKK \u03b2) is a major kinase activated by elevated levels of intracellular calcium. Here we evaluated the functional role of CaMKK \u03b2 in neonatal mice after HI in both acute and chronic survival experiments. Postnatal day ten wild-type (WT) and CaMKK \u03b2 knockout (KO) mouse male pups were subjected to unilateral carotid artery ligation, followed by 40 min of hypoxia (10% O2 in N2). STO-609, a CaMKK inhibitor, was administered intraperitoneally to WT mice at 5 minutes after HI. TTC (2,3,5-triphenyltetrazolium chloride monohydrate) staining was used to assess infarct volume 24 h after HI. CaMKK \u03b2 KO mice had larger infarct volume than WT mice and STO-609 increased the infarct volume in WT mice after HI. In chronic survival experiments, WT mice treated with STO-609 showed increased tissue loss in the ipsilateral hemisphere three weeks after HI. Furthermore, when compared with vehicle-treated mice, they showed poorer functional recovery during the three week survival period, as measured by the wire hang test and corner test. Loss of blood\u2013brain barrier proteins, a reduction in survival protein (Bcl-2), and an increase in pro-apoptotic protein Bax were also seen after HI with CaMKK \u03b2 inhibition. In conclusion, inhibition of CaMKK \u03b2 exacerbated neonatal hypoxia\u2013ischemia injury in mice. Our data suggests that enhancing CaMKK signaling could be a potential target for the treatment of hypoxic\u2013ischemic brain injury.<\/jats:p>","DOI":"10.3390\/ijms20092063","type":"journal-article","created":{"date-parts":[[2019,4,26]],"date-time":"2019-04-26T07:52:59Z","timestamp":1556265179000},"page":"2063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inhibition of Calcium\/Calmodulin-Dependent Protein Kinase Kinase \u03b2 Is Detrimental in Hypoxia\u2013Ischemia Neonatal Brain Injury"],"prefix":"10.3390","volume":"20","author":[{"given":"Jia-Wei","family":"Min","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center, McGovern Medical School, MSER338, 6431 Fannin St, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Bu","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center, McGovern Medical School, MSER338, 6431 Fannin St, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center, McGovern Medical School, MSER338, 6431 Fannin St, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yashasvee","family":"Munshi","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center, McGovern Medical School, MSER338, 6431 Fannin St, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gab Seok","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center, McGovern Medical School, MSER338, 6431 Fannin St, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean P.","family":"Marrelli","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center, McGovern Medical School, MSER338, 6431 Fannin St, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise D.","family":"McCullough","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center, McGovern Medical School, MSER338, 6431 Fannin St, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center, McGovern Medical School, MSER338, 6431 Fannin St, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.neuropharm.2015.07.007","article-title":"Vitexin reduces hypoxia-ischemia neonatal brain injury by the inhibition of HIF-1alpha in a rat pup model","volume":"99","author":"Min","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1056\/NEJMoa1112066","article-title":"Childhood outcomes after hypothermia for neonatal encephalopathy","volume":"366","author":"Shankaran","year":"2012","journal-title":"New Engl. 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