Acetoacetate protects hippocampal neurons against glutamate-mediated neuronal damage during glycolysis inhibition

Neuroscience. 2003;120(2):365-78. doi: 10.1016/s0306-4522(03)00266-5.


Glucose is the main substrate that fulfills energy brain demands. However, in some circumstances, such as diabetes, starvation, during the suckling period and the ketogenic diet, brain uses the ketone bodies, acetoacetate and beta-hydroxybutyrate, as energy sources. Ketone body utilization in brain depends directly on its blood concentration, which is normally very low, but increases substantially during the conditions mentioned above. Glutamate neurotoxicity has been implicated in neurodegeneration associated with brain ischemia, hypoglycemia and cerebral trauma, conditions related to energy failure, and to elevation of glutamate extracellular levels in brain. In recent years substantial evidence favoring a close relation between glutamate neurotoxic potentiality and cellular energy levels, has been compiled. We have previously demonstrated that accumulation of extracellular glutamate after inhibition of its transporters, induces neuronal death in vivo during energy impairment induced by glycolysis inhibition. In the present study we have assessed the protective potentiality of the ketone body, acetoacetate, against glutamate-mediated neuronal damage in the hippocampus of rats chronically treated with the glycolysis inhibitor, iodoacetate, and in hippocampal cultured neurons exposed to a toxic concentration of iodoacetate. Results show that acetoacetate efficiently protects against glutamate neurotoxicity both in vivo and in vitro probably by a mechanism involving its role as an energy substrate.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetoacetates / blood
  • Acetoacetates / pharmacology*
  • Adenosine Triphosphate / analysis
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Survival
  • Cells, Cultured
  • Dicarboxylic Acids / adverse effects
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Administration Routes
  • Drug Administration Schedule
  • Drug Interactions
  • Embryo, Mammalian
  • Enzyme Inhibitors / adverse effects
  • Excitatory Amino Acid Antagonists / pharmacology
  • Female
  • Glutamic Acid / pharmacology
  • Glycolysis / drug effects*
  • Hippocampus / cytology*
  • Hippocampus / drug effects
  • Iodoacetates / adverse effects
  • Male
  • Neurons / drug effects*
  • Neuroprotective Agents / blood
  • Neuroprotective Agents / pharmacology*
  • Neurotransmitter Uptake Inhibitors / adverse effects
  • Pregnancy
  • Pyrrolidines / adverse effects
  • Pyruvic Acid / pharmacology
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Wistar
  • Time Factors


  • Acetoacetates
  • Dicarboxylic Acids
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Iodoacetates
  • Neuroprotective Agents
  • Neurotransmitter Uptake Inhibitors
  • Pyrrolidines
  • Quinoxalines
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Glutamic Acid
  • acetoacetic acid
  • Dizocilpine Maleate
  • Pyruvic Acid
  • Adenosine Triphosphate
  • pyrrolidine-2,4-dicarboxylic acid