title: Ketone bodies are protective against oxidative stress in neocortical neurons.
abstract: Ketone bodies (KB) have been shown to prevent neurodegeneration in models of Parkinson's and Alzheimer's diseases, but the mechanisms underlying these effects remain unclear. One possibility is that KB may exert antioxidant activity. In the current study, we explored the effects of KB on rat neocortical neurons exposed to hydrogen peroxide (H(2)O(2)) or diamide - a thiol oxidant and activator of mitochondrial permeability transition (mPT). We found that: (i) KB completely blocked large inward currents induced by either H(2)O(2) or diamide; (ii) KB significantly decreased the number of propidium iodide-labeled cells in neocortical slices after exposure to H(2)O(2) or diamide; (iii) KB significantly decreased reactive oxygen species (ROS) levels in dissociated neurons and in isolated neocortical mitochondria; (iv) the electrophysiological effects of KB in neurons exposed to H(2)O(2) or diamide were mimicked by bongkrekic acid and cyclosporin A, known inhibitors of mPT, as well as by catalase and DL - dithiothreitol, known antioxidants; (v) diamide alone did not significantly alter basal ROS levels in neurons, supporting previous studies indicating that diamide-induced neuronal injury may be mediated by mPT opening; and (vi) KB significantly increased the threshold for calcium-induced mPT in isolated mitochondria. Taken together, our data suggest that KB may prevent mPT and oxidative injury in neocortical neurons, most likely by decreasing mitochondrial ROS production.
authors.affiliation: Barrow Neurological Institute and St. Joseph's Hospital & Medical Center, Phoenix, Arizona 85013, USA.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Kim
authors.forename: Laurie M
authors.initials: LM
authors.lastname: Davis
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
authors.forename: Marwan
authors.initials: M
authors.lastname: Maalouf
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Simeone
authors.forename: Johannes
authors.initials: J
authors.lastname: van Brederode
authors.forename: Jong M
authors.initials: JM
authors.lastname: Rho
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007657:Ketone Bodies / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D019579:Neocortex / Q000166:cytology*; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D007657:Ketone Bodies; D017382:Reactive Oxygen Species; D011419:Propidium; D006861:Hydrogen Peroxide; D002374:Catalase