{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T08:16:19Z","timestamp":1762157779203,"version":"3.37.3"},"reference-count":73,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,3,30]],"date-time":"2018-03-30T00:00:00Z","timestamp":1522368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology, Japan","doi-asserted-by":"crossref","award":["25461641","16K10106"],"award-info":[{"award-number":["25461641","16K10106"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl J of Devlp Neuroscience"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Despite the recent progress of perinatal medicine, perinatal hypoxic\u2010ischemic (HI) insult remains an important cause of brain injury in neonates, and is pathologically characterized by neuronal loss and the presence of microglia. Neurotransmitters, such as norepinephrine (NE) and glutamate, are involved in the pathogenesis of hypoxic\u2010ischemic encephalopathy <jats:italic>via<\/jats:italic> the interaction between neurons and microglia. Although it is well known that the monoamine neurotransmitter NE acts as an anti\u2010inflammatory agent in the brain under pathological conditions, its effects on perinatal HI insult remains elusive. Atomoxetine, a selective NE reuptake inhibitor, has been used clinically for the treatment of attention\u2010deficit hyperactivity disorder in children. Here, we investigated whether the enhancement of endogenous NE by administration of atomoxetine could protect neonates against HI insult by using the neonatal male rat model. We also examined the involvement of microglia in this process.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Unilateral HI brain injury was induced by the combination of left carotid artery dissection followed by ligation and hypoxia (8% O<jats:sub>2<\/jats:sub>, 2\u202fh) in postnatal day 7 (P7) male rat pups. The pups were randomized into three groups: the atomoxetine treatment immediately after HI insult, the atomoxetine treatment at 3\u202fh after HI insult, or the vehicle treatment group. The pups were euthanized on P8 and P14, and the brain regions including the cortex, striatum, hippocampus, and thalamus were evaluated by immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HI insult resulted in severe brain damage in the ipsilateral hemisphere at P14. Atomoxetine treatment immediately after HI insult significantly increased NE levels in the ipsilateral hemisphere at 1\u202fh after HI insult and reduced the neuronal damage <jats:italic>via<\/jats:italic> the increased phosphorylation of cAMP response element\u2010binding protein (pCREB) in all brain regions examined. In addition, the number of microglia was maintained under atomoxetine treatment compared with that of the vehicle treatment group. To determine the involvement of microglia in the process of neuronal loss by HI insult, we further examined the influence of hypoxia on rat primary cultured microglia by the quantitative real\u2010time polymerase chain reaction. Hypoxia did not cause the upregulation of interleukin\u20101beta (IL\u20101\u03b2)\u202fmRNA expression, but decreased the microglial intrinsic nitric oxide synthase (iNOS)\/arginase1 mRNA expression ratio. NE treatment further decreased the microglial iNOS\/arginase1 mRNA expression ratio. In contrast, no significant neuroprotective effect was observed at P14 when atomoxetine was administered at 3\u202fh after HI insult.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings suggested that the enhancement of intrinsic neurotransmitter NE signaling by a selective NE reuptake inhibitor, atomoxetine, reduced the perinatal HI insult brain injury. In addition, atomoxetine treatment was associated with changes of TUNEL, pCREB, and BDNF expression levels, and microglial numbers, morphology, and responses.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.ijdevneu.2018.03.011","type":"journal-article","created":{"date-parts":[[2018,3,31]],"date-time":"2018-03-31T00:24:15Z","timestamp":1522455855000},"page":"34-45","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Atomoxetine, a selective norepinephrine reuptake inhibitor, improves short\u2010term histological outcomes after hypoxic\u2010ischemic brain injury in the neonatal male rat"],"prefix":"10.1002","volume":"70","author":[{"given":"Masatake","family":"Toshimitsu","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology Graduate School of Medicine, University of Tokyo Tokyo 113\u20108655 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshimasa","family":"Kamei","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Graduate School of Medicine, University of Tokyo Tokyo 113\u20108655 Japan"},{"name":"Department of Obstetrics and Gynecology Saitama Medical University Hospital Saitama 350\u20100495 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Ichinose","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Graduate School of Medicine, University of Tokyo Tokyo 113\u20108655 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Seyama","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Graduate School of Medicine, University of Tokyo Tokyo 113\u20108655 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Imada","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Graduate School of Medicine, University of Tokyo Tokyo 113\u20108655 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Iriyama","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Graduate School of Medicine, University of Tokyo Tokyo 113\u20108655 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Graduate School of Medicine, University of Tokyo Tokyo 113\u20108655 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,3,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1159\/000435858","article-title":"The role of activated microglia and resident macrophages in the neurovascular unit during cerebral ischemia: is the jury still Out?","volume":"25","author":"Barakat R.","year":"2016","journal-title":"Med. 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