title: In vivo 2-deoxyglucose administration preserves glucose and glutamate transport and mitochondrial function in cortical synaptic terminals after exposure to amyloid beta-peptide and iron: evidence for a stress response.
abstract: Mild metabolic stress can increase resistance of neurons in the brain to subsequent more severe insults, as exemplified by the beneficial effects of heat shock and ischemic preconditioning. Studies of Alzheimer's disease and other age-related neurodegenerative disorders indicate that dysfunction and degeneration of synapses occur early in the cell death process, and that oxidative stress and mitochondrial dysfunction are central events in this pathological process. It was recently shown that administration of 2-deoxy-d-glucose (2DG), a nonmetabolizable glucose analog that induces metabolic stress, to rats and mice can increase resistance of neurons in the brain to excitotoxic, ischemic, and oxidative injury. We now report that administration of 2DG to adult rats (daily i.p. injections of 100 mg/kg body weight) increases resistance of synaptic terminals to dysfunction and degeneration induced by amyloid beta-peptide and ferrous iron, an oxidative insult. The magnitude of impairment of glucose and glutamate transport induced by amyloid beta-peptide and iron was significantly reduced in cortical synaptosomes from 2DG-treated rats compared to saline-treated control rats. Mitochondrial dysfunction, as indicated by increased levels of reactive oxygen species and decreased transmembrane potential, was significantly attenuated after exposure to amyloid beta-peptide and iron in synaptosomes from 2DG-treated rats. Levels of the stress proteins HSP-70 and GRP-78 were increased in synaptosomes from 2DG-treated rats, suggesting a mechanism whereby 2DG protects synaptic terminals. We conclude that 2DG bolsters cytoprotective mechanisms within synaptic terminals, suggesting novel preventative and therapeutic approaches for neurodegenerative disorders.
authors.affiliation: Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
authors.forename: Z H
authors.initials: ZH
authors.lastname: Guo
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003847:Deoxyglucose / Q000494:pharmacology* / Q000627:therapeutic use; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006360:Heat-Shock Proteins; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018832:Molecular Chaperones / Q000187:drug effects / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000139:chemically induced* / Q000503:physiopathology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009004:Monosaccharide Transport Proteins; D003847:Deoxyglucose