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.

5 Reads
  • Source
    • "However, recent reports using more sensitive methods indicate that autophagy is indeed induced in primary neuronal Fig. 3. Effects of CR, FR and IF on some neurodegenerative conditions. The sizes of the rectangles represent the relative number of publications for each pathology (numbers are in parenthesis), summarized from the following: Anson et al. [3], Armentero et al. [4], Arumugam et al. [5], Azarbar et al. [7], Bhattacharya et al. [10], Bough et al. [13], Bough et al. [14], Bruce-Keller et al. [18], Contestabile et al. [27], Costantini et al. [29], Dhurandar et al. [32], Duan and Mattson [34], Duan et al. [33], Eagles et al. [35], Greene et al. [45], Griffioen et al. [46], Halagappa et al. [48], Hamadeh and Tarnopolsky [49], Hamadeh et al. [50], Hartman et al. [52], Holmer et al. [53], Kumar et al. [58], Lee et al. [58], Liu et al. [62], Mantis et al. [64], Mouton et al. [74], Parinejad et al. [80], Patel et al. [81], Patel et al. [79], Pedersen and Mattson [82], Qin et al. [85], Qin et al. [86], Qiu et al. [88], Wang et al. [98], Wu et al. [99], Yoon et al. [102], Yu and Mattson [103], Zhu et al. [105] "
    [Show abstract] [Hide abstract]
    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(1). DOI:10.1016/j.redox.2013.12.021
  • Source
    • "To assess the effects of a ketogenic state on outcome following cerebral ischemia, the majority of studies utilized various models to induce cerebral ischemia; thirteen used vessel occlusion (filament occlusion of the middle cerebral artery, or clip occlusion of a number of vessels including the middle cerebral artery), one study used microspheres (Gueldry et al. 1990), one study used a model of glutamate excitotoxicity via application of iodoacetate (Massieu et al. 2003), and one study used a hypoxic chamber (Xu et al. 2010). Male rat models (F344, Long Evans, Sprague- Dawley, Wistar) were used in 12 of the 16 studies; the remaining four used either a mouse strain (Suzuki et al. 2001; Arumugam et al. 2010; Yoon et al. 2011) or gerbils (McEwen and Paterson 2010). "
    [Show abstract] [Hide abstract]
    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(s2):52-7. DOI:10.1111/j.1471-4159.2012.07943.x · 4.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 &amp Cellular Proteomics 02/2013; 12(6). DOI:10.1074/mcp.R112.024869 · 6.56 Impact Factor

Similar Publications