Energy Restriction Negates NMDA Receptor Antagonist Efficacy in Ischemic Stroke
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.
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ABSTRACT: The brain has a central role in the regulation of energy stability of the organism. It is the organ with the highest energetic demands, the most susceptible to energy deficits, and is responsible for coordinating behavioral and physiological responses related to food foraging and intake. Dietary interventions have been shown to be a very effective means to extend lifespan and delay the appearance of age-related pathological conditions, notably those associated with brain functional decline. The present review focuses on the effects of these interventions on brain metabolism and cerebral redox state, and summarizes the current literature dealing with dietary interventions on brain pathology.01/2014; 2. DOI:10.1016/j.redox.2013.12.021
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ABSTRACT: As a predictor of potential clinical outcome, we performed a systematic review of controlled studies that assessed experimental stroke outcome in rodents maintained on special diets (calorie restriction and ketogenic diet) or following the direct administration of ketone bodies. Pre-clinical studies were identified by searching web databases and the reference lists of relevant original articles and reviews. Sixteen published studies (a total of 733 experimental animals) met specific criteria and were analyzed using Cochrane Review Manager software. This resulted in objective evidence to suggest beneficial effects of the ketogenic pathway on pathological and functional outcomes following experimental stroke.Journal of Neurochemistry 11/2012; 123 Suppl 2:52-7. DOI:10.1111/j.1471-4159.2012.07943.x · 4.24 Impact Factor
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ABSTRACT: The separation between biological and technical variation without extensive use of technical replicates is often challenging, particularly in the context of different forms of protein and peptide modifications. Biosampling procedures in the research laboratory are easier to conduct within a shorter time frame and under controlled conditions as compared to clinical sampling with the later often having issues of reproducibility. But is the research laboratory biosampling really less variable? Biosampling introduces within minutes rapid tissue specific changes in the cellular microenvironment; inducing a range of different pathways associated with cell survival. Biosampling involves hypoxia and hypothermia which are circumstances for which there are evolutionary conserved defense strategies in range of species and also are relevant for a range of biomedical conditions. It remains unclear to what extent such adaptive processes are reflected in different biosampling procedures or how important they are for the definition of sample quality. Lately, an increasing number of comparative studies on different biosampling approaches, post-mortem effects and pre-sampling biological state have investigated such immediate early biosampling effects. Commonalities between biosampling effects and a range of ischemia/reperfusion and hypometabolism/anoxia associated biological phenomena indicate that even small variations in post-sampling time intervals are likely to introduce a set of non-random and tissue specific effects of experimental importance (both in vivo and in vitro). This review integrates the information provided by these comparative studies and discusses how an adaptive biological perspective in biosampling procedures may be relevant for sample quality issues.Molecular & Cellular Proteomics 02/2013; DOI:10.1074/mcp.R112.024869 · 7.25 Impact Factor