D-β-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures

Authors

  • R. Masuda,

    1. Laboratory of Metabolic Control/National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, DHHS, Bethesda, Maryland
    Current affiliation:
    1. Department of Neurology, School of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan
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  • J.W. Monahan,

    1. Laboratory of Metabolic Control/National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, DHHS, Bethesda, Maryland
    Current affiliation:
    1. Cell and Molecular Biology Laboratory, Department of Natural Science, DeSales University, Pennsylvania
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  • Y. Kashiwaya

    Corresponding author
    1. Laboratory of Metabolic Control/National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, DHHS, Bethesda, Maryland
    • Laboratory of Metabolic Control/National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, DHHS, 5625 Fishers Lane, Rm 2S28, Bethesda, MD 20892
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  • This article is a US Government work and, as such, is in the Public domain in the United States of America.

Abstract

Hypoxia decreased survival of cultured rat primary hippocampal neurons in a time dependent manner. Addition of 4 mM Na D-β-hydroxybutyrate (bHB), a ketone body, protected the cells for 2 hr and maintained the increase in survival compared to that of controls for up to 6 hr. Trypan blue exclusion indicated that acute cell death was reduced markedly after 2-hr exposure to hypoxia in the bHB-treated group. The presence of bHB also decreased the number of neurons exhibiting condensed nuclei visualized by propidium iodide, indicative of apoptosis. The mitochondrial transmembrane potential (Em/c) was maintained for up to 2 hr exposure to hypoxia in the bHB-treated group, whereas the potential in the control group was decreased. Furthermore, cytochrome C release, caspase-3 activation, and poly (ADP-ribose) polymerase (PARP) cleavage were decreased in the bHB-treated group for the first 2 hr of exposure. These findings indicate that ketone bodies may be a candidate for widening the therapeutic window before thrombolytic therapy and at the same time decreasing apoptotic damage in the ischemic penumbra. © 2005 Wiley-Liss, Inc.

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