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Augmentation of Normal and Glutamate-Impaired Neuronal Respiratory Capacity by Exogenous Alternative Biofuels

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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.

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Artificial cerebrospinal fluid


2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid




Adenosine triphosphate






Day in vitro


Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone


(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate


N-methyl d-aspartate


Oxygen consumption rate


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This work was supported by NIH grants T32-NS-07375 to M.D.L., P01-HD16596 to G.F., and R01-NS064978 to B.M.P. The authors thank Ms. Sausan Jaber for performing the cell immunohistochemistry measurements.

Conflict of Interest

Melissa Laird declares that she has no conflict of interest. Pascaline Clerc declares that she has not conflict of interests. Brian Polster declares that he has no conflict of interest. Gary Fiskum declares that he has no conflict of interest.

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Correspondence to Gary Fiskum.

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All institutional and national guidelines for the care and use of laboratory animals were followed.

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Laird, M.D., Clerc, P., Polster, B.M. et al. Augmentation of Normal and Glutamate-Impaired Neuronal Respiratory Capacity by Exogenous Alternative Biofuels. Transl. Stroke Res. 4, 643–651 (2013).

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