Energy Restriction Negates NMDA Receptor Antagonist Efficacy in Ischemic Stroke
- 223 Downloads
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.
KeywordsCerebral ischemia Diabetes Dizocilpine Excitotoxicity MK-801 Obesity
- 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