D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures.
Hypoxia decreased survival of cultured rat primary hippocampal neurons in a time dependent manner. Addition of 4 mM Na D-beta-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.
Masuda
R
R
Laboratory of Metabolic Control/National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, DHHS, Bethesda, Maryland 20892, USA.
Monahan
J W
JW
Kashiwaya
Y
Y
D020155:3-Hydroxybutyric Acid / Q000494:pharmacology*; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D007150:Immunohistochemistry / Q000379:methods; D008564:Membrane Potentials / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011419:Propidium; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D013997:Time Factors; D014343:Trypan Blue
D016895:Culture Media, Serum-Free; D005904:Glial Fibrillary Acidic Protein; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D011419:Propidium; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D014343:Trypan Blue; D020155:3-Hydroxybutyric Acid