title: Augmentation of normal and glutamate-impaired neuronal respiratory capacity by exogenous alternative biofuels.
abstract: Mitochondrial respiratory capacity is critical for responding to changes in neuronal energy demand. One approach toward neuroprotection is the administration of alternative energy substrates ("biofuels") to overcome brain injury-induced inhibition of glucose-based aerobic energy metabolism. This study tested the hypothesis that exogenous pyruvate, lactate, β-hydroxybutyrate, and acetyl-L-carnitine each increase neuronal respiratory capacity in vitro either in the absence of or following transient excitotoxic glutamate receptor stimulation. Compared to the presence of 5 mM glucose alone, the addition of pyruvate, lactate, or β-hydroxybutyrate (1.0-10.0 mM) to either day in vitro (DIV) 14 or 7 rat cortical neurons resulted in significant, dose-dependent stimulation of respiratory capacity, measured by cell respirometry as the maximal O2 consumption rate in the presence of the respiratory uncoupler carbonyl cyanide-p-trifluoromethoxyphenylhydrazone. A 30-min exposure to 100 μM glutamate impaired respiratory capacity for DIV 14, but not DIV 7, neurons. Glutamate reduced the respiratory capacity for DIV 14 neurons with glucose alone by 25 % and also reduced respiratory capacity with glucose plus pyruvate, lactate, or β-hydroxybutyrate. However, respiratory capacity in glutamate-exposed neurons following pyruvate or β-hydroxybutyrate addition was still, at least, as high as that obtained with glucose alone in the absence of glutamate exposure. These results support the interpretation that previously observed neuroprotection by exogenous pyruvate, lactate, or β-hydroxybutyrate is at least partially mediated by their preservation of neuronal respiratory capacity.
authors: Department of Anesthesiology and the Shock Trauma and Anesthesiology Research Center, School of Medicine, University of Maryland, 685 W. Baltimore St., Baltimore, MD 21201, USA.
authors: Melissa D
authors: MD
authors: Laird
authors: Pascaline
authors: P
authors: Clerc
authors: Brian M
authors: BM
authors: Polster
authors: Gary
authors: G
authors: Fiskum
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000108:Acetylcarnitine / Q000494:pharmacology; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects*; D061209:Proton Ionophores / Q000494:pharmacology; D019289:Pyruvic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism
chemical_list: D018697:Nootropic Agents; D061209:Proton Ionophores; D017470:Receptors, Glutamate; D019344:Lactic Acid; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D018698:Glutamic Acid; D000108:Acetylcarnitine; D019289:Pyruvic Acid; D020155:3-Hydroxybutyric Acid