NeuroMolecular Medicine

, 13:175 | Cite as

Energy Restriction Negates NMDA Receptor Antagonist Efficacy in Ischemic Stroke

  • Jeong Seon Yoon
  • Mohamed R. Mughal
  • Mark P. Mattson
Original Paper


Preclinical evaluation of drugs for neurological disorders is usually performed on overfed rodents, without consideration of how metabolic state might affect drug efficacy. Using a widely employed mouse model of focal ischemic stroke, we found that that the NMDA receptor antagonist dizocilpine (MK-801) reduces brain damage and improves functional outcome in mice on the usual ad libitum diet, but exhibits little or no therapeutic efficacy in mice maintained on an energy-restricted diet. Thus, NMDA receptor activation plays a central role in the mechanism by which a high dietary energy intake exacerbates ischemic brain injury. These findings suggest that inclusion of subjects with a wide range of energy intakes in clinical trials for stroke may mask a drug benefit in the overfed/obese subpopulation of subjects.


Cerebral ischemia Diabetes Dizocilpine Excitotoxicity MK-801 Obesity 



This work was supported by the Intramural Research Program of the National Institute on Aging.

Conflicts of interest

Nothing to report.


  1. Albers, G. W., Goldstein, L. B., Hall, D., Lesko, L. M., & Aptiganel Acute Stroke Investigators. (2001). Aptiganel hydrochloride in acute ischemic stroke: A randomized controlled trial. JAMA, 286, 2673–2682.PubMedCrossRefGoogle Scholar
  2. Arumugam, T. V., Phillips, T. M., Cheng, A., Morrell, C. H., Mattson, M. P., & Wan, R. (2010). Age and energy intake interact to modify cell stress pathways and stroke outcome. Annals of Neurology, 67, 41–52.PubMedCrossRefGoogle Scholar
  3. Boxer, P. A., Cordon, J. J., Mann, M. E., Rodolosi, L. C., Vartanian, M. G., Rock, D. M., et al. (1990). Comparison of phenytoin with noncompetitive N-methyl-d-aspartate antagonists in a model of focal brain ischemia in rat. Stroke, 21, S47–S51.CrossRefGoogle Scholar
  4. Cheng, B., & Mattson, M. P. (1994). NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Research, 640, 56–67.PubMedCrossRefGoogle Scholar
  5. Hyun, D. H., Emerson, S. S., Jo, D. G., Mattson, M. P., & de Cabo, R. (2006). Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. Proceedings of the National Academy of Sciences USA, 103, 19908–199912.CrossRefGoogle Scholar
  6. Kochhar, A., Zivin, J. A., Lyden, P. D., & Mazzarella, V. (1988). Glutamate antagonist therapy reduces neurologic deficits produced by focal central nervous system ischemia. Archives of Neurology, 45, 148–153.PubMedGoogle Scholar
  7. Ma, J., Endres, M., & Moskowitz, M. A. (1998). Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice. British Journal of Pharmacology, 124, 756–762.PubMedCrossRefGoogle Scholar
  8. Martin, B., Ji, S., Maudsley, S., & Mattson, M. P. (2010). “Control” laboratory rodents are metabolically morbid: Why it matters. Proceedings of the National Academy of Sciences USA, 107, 6127–6133.CrossRefGoogle Scholar
  9. Martin, B., Mattson, M. P., & Maudsley, S. (2006). Caloric restriction and intermittent fasting: Two potential diets for successful brain aging. Ageing Research Reviews, 5, 332–353.PubMedCrossRefGoogle Scholar
  10. Mattson, M. P., Lovell, M. A., Furukawa, K., & Markesbery, W. R. (1995). Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2 + concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. Journal of Neurochemistry, 65, 1740–1751.PubMedCrossRefGoogle Scholar
  11. Minematsu, K., Fisher, M., Li, L., Davis, M. A., Knapp, A. G., Cotter, R. E., et al. (1993). Effects of a novel NMDA antagonist on experimental stroke rapidly and quantitatively assessed by diffusion-weighted MRI. Neurology, 43, 397–403.PubMedGoogle Scholar
  12. Robertson, C., Goodman, J. C., Grossman, R. G., Claypool, M., & White, A. (1992). Dietary nonprotein calories and cerebral infarction size in rats. Stroke, 23, 564–568.PubMedCrossRefGoogle Scholar
  13. Stranahan, A. M., Lee, K., Martin, B., Maudsley, S., Golden, E., Cutler, R. G., et al. (2009). Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice. Hippocampus, 19, 951–961.PubMedCrossRefGoogle Scholar
  14. Tureyen, K., Bowen, K., Liang, J., Dempsey, R. J., & Vemuganti, R. (2011). Exacerbated brain damage, edema and inflammation in type-2 diabetic mice subjected to focal ischemia. Journal of Neurochemistry, 116, 499–507.PubMedCrossRefGoogle Scholar
  15. Uranga, R. M., Bruce-Keller, A. J., Morrison, C. D., Fernandez-Kim, S. O., Ebenezer, P. J., Zhang, L., et al. (2010). Intersection between metabolic dysfunction, high fat diet consumption, and brain aging. Journal of Neurochemistry, 114, 344–361.PubMedGoogle Scholar
  16. Yoon, J. S., Lee, J. H., Son, T. G., Mughal, M. R., Greig, N. H., & Mattson, M. P. (2011). Pregabalin suppresses calcium-mediated proteolysis and improves stroke outcome. Neurobiology of Disease, 41, 624–629.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2011

Authors and Affiliations

  • Jeong Seon Yoon
    • 1
  • Mohamed R. Mughal
    • 1
  • Mark P. Mattson
    • 1
    • 2
  1. 1.Laboratory of NeurosciencesNational Institute on Aging Intramural Research ProgramBaltimoreUSA
  2. 2.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations