Original Paper

NeuroMolecular Medicine

, 13:175

First online:

Energy Restriction Negates NMDA Receptor Antagonist Efficacy in Ischemic Stroke

  • Jeong Seon YoonAffiliated withLaboratory of Neurosciences, National Institute on Aging Intramural Research Program
  • , Mohamed R. MughalAffiliated withLaboratory of Neurosciences, National Institute on Aging Intramural Research Program
  • , Mark P. MattsonAffiliated withLaboratory of Neurosciences, National Institute on Aging Intramural Research ProgramDepartment of Neuroscience, Johns Hopkins University School of Medicine Email author 

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Abstract

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.

Keywords

Cerebral ischemia Diabetes Dizocilpine Excitotoxicity MK-801 Obesity