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Hypoxic-ischemic brain injury exacerbates neuronal apoptosis and precipitates spontaneous seizures in glucose transporter isoform 3 heterozygous null mice

Authors

  • Camille Fung,

    1. Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, California
    2. Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, California
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  • Edward Evans,

    1. Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, California
    2. Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, California
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  • Don Shin,

    1. Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, California
    2. Division of Neurology, David Geffen School of Medicine UCLA, Los Angeles, California
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  • Bo-Chul Shin,

    1. Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, California
    2. Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, California
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  • Yuanzi Zhao,

    1. Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, California
    2. Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, California
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  • Raman Sankar,

    1. Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, California
    2. Division of Neurology, David Geffen School of Medicine UCLA, Los Angeles, California
    3. Department of Neurology, David Geffen School of Medicine UCLA, Los Angeles, California
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  • Gautam Chaudhuri,

    1. Department of Obstetrics and Gynecology, David Geffen School of Medicine UCLA, Los Angeles, California
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  • Sherin U. Devaskar

    Corresponding author
    1. Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, California
    2. Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, California
    • 10833 Le Conte Avenue, MDCC-B2-375, Los Angeles, CA 90095-1752

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Abstract

We examined the effects of 45-min hypoxia (FiO2 0.08; Hx) vs. normoxia (FiO2 0.21; Nx) on the ipsilateral (Ipsi) and contralateral (Ctrl) sides of the brain in neuronal glucose transporter isoform 3 (Glut3) heterozygous null mice (glut3+/−) and their wild-type littermates (WT), undergoing unilateral carotid artery ligation. Glut3+/− mice, under Nx, demonstrated a compensatory increase in blood–brain barrier/glial Glut1 protein concentration and a concomitant increase in neuronal nitric oxide synthase (nNOS) enzyme activity and Bax protein, with a decrease in procaspase 3 protein (P < 0.05 each). After Hx, reoxygenation in FiO2 of 0.21 led to no comparable adaptive up-regulation of the ipsilateral brain Glut3 or Glut1 protein at 4 hr and Glut1 at 24 hr in glut3+/− vs. WT. These brain Glut changes in glut3+/− but not WT mice were associated with an increase in proapoptotic Bax protein and caspase-3 enzyme activity (P < 0.01 each) and a decline in the antiapoptotic Bcl-2 and procaspase-3 proteins (P < 0.05 each). Glut3+/− mice after Hx demonstrated TUNEL-positive neurons with nuclear pyknosis in most ipsilateral (hypoxic-ischemia) brain regions. A subset (∼55%) of glut3+/− mice developed spontaneous seizures after hypoxic-ischemia, confirmed by electroencephalography, but the WT mice remained seizure-free. Pentylenetetrazole testing demonstrated an increased occurrence of longer lasting clinical seizures at a lower threshold in glut3+/− vs. WT mice, with no detectable differences in monamine neurotransmitters. We conclude that hypoxic-ischemic brain injury in glut3+/− mice exacerbates cellular apoptosis and necrosis and precipitates spontaneous seizures. © 2010 Wiley-Liss, Inc.

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