Energy Restriction Negates NMDA Receptor Antagonist Efficacy in Ischemic Stroke

Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
Neuromolecular medicine (Impact Factor: 3.68). 06/2011; 13(3):175-8. DOI: 10.1007/s12017-011-8145-y
Source: PubMed


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.

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