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Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death

Authors

  • Patrick G. Sullivan PhD,

    1. Department of Neurobiology and Behavior, University of California at Irvine, Irvine, CA
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  • Celine Dubé PhD,

    1. Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA
    2. Department of Pediatrics, University of California at Irvine, Irvine, CA
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  • Kristina Dorenbos BS,

    1. Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA
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  • Oswald Steward PhD,

    1. Department of Neurobiology and Behavior, University of California at Irvine, Irvine, CA
    2. Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA
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  • Tallie Z. Baram MD, PhD

    Corresponding author
    1. Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA
    2. Department of Pediatrics, University of California at Irvine, Irvine, CA
    • Departments of Anatomy and Neurobiology and Pediatrics, University of California at Irvine, Med. Sci. I, 4475, UCI, Irvine, CA 92697-4475
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Abstract

Excitotoxic cell death is the fundamental process responsible for many human neurodegenerative disorders, yet the basic mechanisms involved are not fully understood. Here, we exploited the fact that the immature brain is remarkably resistant to seizure-induced excitotoxic cell death and examined the underlying protective mechanisms. We found that, unlike in the adult, seizures do not increase the formation of reactive oxygen species or result in mitochondrial dysfunction in neonatal brain, because of high levels of the mitochondrial uncoupling protein (UCP2). UCP2 expression and function were basally increased in neonatal brain by the fat-rich diet of maternal milk, and substituting a low-fat diet reduced UCP2, restored mitochondrial coupling, and permitted seizure-induced neuronal injury. Thus, modulation of UCP2 expression and function by dietary fat protects neonatal neurons from excitotoxicity by preventing mitochondrial dysfunction. This mechanism offers novel neuroprotective strategies for individuals, greater than 1% of the world's population, who are affected by seizures. Ann Neurol 2003

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