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@ARTICLE{Ehlting:165129,
      author       = {Ehlting, Anne and Zweyer, Margit and Maes, Elke and
                      Schleehuber, Yvonne and Doshi, Hardik and Sabir, Hemmen and
                      Bernis, Maria Eugenia},
      title        = {{I}mpact of {H}ypoxia-{I}schemia on {N}eurogenesis and
                      {S}tructural and {F}unctional {O}utcomes in a
                      {M}ild-{M}oderate {N}eonatal {H}ypoxia-{I}schemia {B}rain
                      {I}njury {M}odel.},
      journal      = {Life},
      volume       = {12},
      number       = {8},
      issn         = {2075-1729},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DZNE-2022-01436},
      pages        = {1164},
      year         = {2022},
      note         = {CC BY: https://creativecommons.org/licenses/by/4.0/},
      abstract     = {Hypoxic-ischemic encephalopathy (HIE) is a common type of
                      brain injury caused by a lack of oxygen and blood flow to
                      the brain during the perinatal period. The incidence of HIE
                      is approximately 2-3 cases per 1000 live births in
                      high-income settings; while in low- and middle-income
                      countries, the incidence is 3-10-fold higher. Therapeutic
                      hypothermia (TH) is the current standard treatment for
                      neonates affected by moderate-severe HIE. However, more than
                      $50\%$ of all infants with suspected HIE have mild
                      encephalopathy, and these infants are not treated with TH
                      because of their lower risk of adverse outcomes. Despite
                      this, several analyses of pooled data provide increasing
                      evidence that infants who initially have mild encephalopathy
                      may present signs of more significant brain injury later in
                      life. The purpose of this study was to expand our knowledge
                      about the effect of mild-moderate hypoxia-ischemia (HI) at
                      the cellular, structural, and functional levels. An
                      established rat model of mild-moderate HI was used, where
                      postnatal day (P) 7 rats were exposed to unilateral
                      permanent occlusion of the left carotid artery and 90 min of
                      $8\%$ hypoxia, followed by TH or normothermia (NT)
                      treatment. The extent of injury was assessed using histology
                      (P14 and P42) and MRI (P11 and P32), as well as with
                      short-term and long-term behavioral tests. Neurogenesis was
                      assessed by BrdU staining. We showed that mild-moderate HI
                      leads to a progressive loss of brain tissue, pathological
                      changes in MRI scans, as well as an impairment of long-term
                      motor function. At P14, the median area loss assessed by
                      histology for HI animals was $20\%$ (p < 0.05),
                      corresponding to mild-moderate brain injury, increasing to
                      $55\%$ (p < 0.05) at P42. The data assessed by MRI
                      corroborated our results. HI led to a decrease in
                      neurogenesis, especially in the hippocampus and the lateral
                      ventricle at early time points, with a delayed partial
                      recovery. TH was not neuroprotective at early time points
                      following mild-moderate HI, but prevented the increase in
                      brain damage over time. Additionally, rats treated with TH
                      showed better long-term motor function. Altogether, our
                      results bring more light to the understanding of
                      pathophysiology following mild-moderate HI. We showed that,
                      in the context of mild-moderate HI, TH failed to be
                      significantly neuroprotective. However, animals treated with
                      TH showed a significant improvement in motor, but not
                      cognitive long-term function. These results are in line with
                      what is observed in some cases where neonates with mild HIE
                      are at risk of neurodevelopmental deficits in infancy or
                      childhood. Whether TH should be used as a preventive
                      treatment to reduce adverse outcomes in mild-HIE remains of
                      active interest, and more research has to be carried out in
                      order to address this question.},
      keywords     = {BrdU (Other) / MRI (Other) / behavior testing (Other) /
                      hypothermia (Other) / hypoxia-ischemia (Other) / mild HIE
                      (Other) / neonatal (Other) / neurogenesis (Other)},
      cin          = {AG Sabir / SAMRI},
      ddc          = {570},
      cid          = {I:(DE-2719)5000032 / I:(DE-2719)1040270},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36013343},
      pmc          = {pmc:PMC9410039},
      doi          = {10.3390/life12081164},
      url          = {https://pub.dzne.de/record/165129},
}