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      Early post-natal exposure to intermittent hypoxia in rodents is pro-inflammatory, impairs white matter integrity and alters brain metabolism

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          Abstract

          Background

          Preterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury.

          Methods

          Rat pups were exposed to IH from P2–P12. Control animals were exposed to room air. Cytokines were analyzed in plasma and brain tissue at P13 and P18. At P20–P22, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were performed.

          Results

          Pups exposed to IH had increased plasma Gro/CXCL1 and cerebellar IFN-γ and IL-1β at P13, and brainstem enolase at P18. DTI showed a decrease in FA and AD in the corpus callosum (CC) and cingulate gyrus and an increase in RD in the CC. MRS revealed decreases in NAA/Cho, Cr, Tau/Cr and Gly/Cr and increases in TCho and GPC in the brainstem and decreases in NAA/Cho in the hippocampus.

          Conclusions

          We conclude that early postnatal exposure to IH, similar in magnitude experienced in human preterm infants, is associated with evidence for pro-inflammatory changes, decreases in white matter integrity, and metabolic changes consistent with hypoxia.

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          Most cited references 46

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          Association Between Intermittent Hypoxemia or Bradycardia and Late Death or Disability in Extremely Preterm Infants.

          Extremely preterm infants may experience intermittent hypoxemia or bradycardia for many weeks after birth. The prognosis of these events is uncertain.
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            Invited review: Physiological and pathophysiological responses to intermittent hypoxia.

            This mini-review summarizes the physiological adaptations to and pathophysiological consequences of intermittent hypoxia with special emphasis given to the pathophysiology associated with obstructive sleep apnea. Intermittent hypoxia is an effective stimulus for evoking the respiratory, cardiovascular, and metabolic adaptations normally associated with continuous chronic hypoxia. These adaptations are thought by some to be beneficial in that they may provide protection against disease as well as improve exercise performance in athletes. The long-term consequences of chronic intermittent hypoxia may have detrimental effects, including hypertension, cerebral and coronary vascular problems, developmental and neurocognitive deficits, and neurodegeneration due to the cumulative effects of persistent bouts of hypoxia. Emphasis is placed on reviewing the available data on intermittent hypoxia, making extensions from applicable information from acute and chronic hypoxia studies, and pointing out major gaps in information linking the genomic and cellular responses to intermittent hypoxia with physiological or pathophysiological responses.
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              Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1.

              In rodents, the chemokine CXCL1 both induces the proliferation and inhibits the migration of oligodendrocyte precursor cells. We previously reported that in multiple sclerosis, the same chemokine is expressed by hypertrophic astrocytes, which associate with oligodendrocytes that express the receptor CXCR2. To investigate whether chemokines influence repair after autoimmune demyelination, we generated GFAP-rtTA x beta-Gal-TRE-CXCL1 double-transgenic (Tg) mice that inducibly overexpress CXCL1 under the control of the astrocyte-specific gene, glial fibrillary acidic protein. Experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, was induced in these animals (and controls) by the subcutaneous injection of myelin oligodendrocyte glycoprotein, and after disease onset, CXCL1 production was initiated by the intraperitoneal injection of doxycycline. Double-Tg animals displayed a milder course of disease compared with both single (CXCL1 or glial fibrillary acidic protein)-Tg and wild-type controls. Pathologies were similar in all groups during the acute stage of disease. During the chronic disease phase, both inflammation and demyelination were diminished in double-Tg mice and Wallerian degeneration was markedly decreased. Remyelination was strikingly more prominent in double-Tg mice, together with an apparent increased number of oligodendrocytes. Moreover, cell proliferation, indicated by BrdU incorporation within the central nervous system, was more widespread in the white matter of double-Tg animals. These findings suggest a neuroprotective role for CXCL1 during the course of autoimmune demyelination.
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                Author and article information

                Journal
                0100714
                6400
                Pediatr Res
                Pediatr. Res.
                Pediatric research
                0031-3998
                1530-0447
                21 April 2017
                03 May 2017
                July 2017
                03 November 2017
                : 82
                : 1
                : 164-172
                Affiliations
                [1 ]Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH
                [2 ]Department of Pediatrics, Geisel School of Medicine at Dartmouth, Lebanon, NH
                [3 ]Biomedical NMR Research Center, Department of Radiology, Geisel School of Medicine at Dartmouth, Lebanon, NH
                [4 ]Children’s National Medical Center and George Washington University, Washington, DC
                [5 ]American SIDS Institute, Naples, FL
                [6 ]Department of Pediatrics, Uniformed Services University, Bethesda, MD
                Author notes
                Corresponding Author: Robert A. Darnall, MD, Department of Molecular and Systems Biology, Dartmouth Geisel School of Medicine, Borwell Building, 1 Medical Center Drive, Lebanon, New Hampshire, USA, robert.a.darnall@ 123456dartmouth.edu , 603-650-6385
                Article
                NIHMS865697
                10.1038/pr.2017.102
                5509485
                28388601

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                Pediatrics

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