title: Alzheimer' s disease, oxidative stress and gammahydroxybutyrate.
abstract: Although the cause of Alzheimer's disease is unknown, oxidative stress, energy depletion, excitotoxicity and vascular endothelial pathology are all considered to play a part in its pathogenesis. In reaction to these adverse events, the Alzheimer brain appears to deploy a highly conserved biological response to tissue stress. Oxidative metabolism is turned down, the expression of antioxidative enzymes is increased and intermediary metabolism is shifted in the direction of the pentose phosphate shunt to promote reductive detoxification, repair and biosynthesis. Gathering evidence suggests that the release of beta-amyloid and the formation of neurofibrillary tangles, the two hallmarks of Alzheimer's disease, are components of this protective response. Gammahydroxybutyrate (GHB), an endogenous short chain fatty acid, may be able to buttress this response. GHB can reduce glucose utilization, shift intermediary metabolism in the direction the pentose phosphate shunt and generate NADPH, a key cofactor in the activity of many antioxidative and reductive enzymes. GHB has been shown to spare cerebral energy utilization, block excitotoxicity and maintain vascular integrity in the face of impaired perfusion. Most important, GHB has repeatedly been shown to prevent the tissue damaging effects of oxidative stress. It may therefore be possible to utilize GHB to strengthen the brain's innate defences against the pathological processes operating in the Alzheimer brain and, in this way, stem the advance of Alzheimer's disease.
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. m.mamelak@utoronto.ca <m.mamelak@utoronto.ca>
authors.forename: Mortimer
authors.initials: M
authors.lastname: Mamelak
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology*; D004734:Energy Metabolism; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D012978:Sodium Oxybate / Q000378:metabolism*
chemical_list: D012978:Sodium Oxybate