Abstract
While interest toward caloric restriction (CR) in various models of brain injury has increased in recent decades, studies have predominantly focused on the benefits of chronic or intermittent CR. The effects of ultra-short, including overnight, CR on acute ischemic brain injury are not well studied. Here, we show that overnight caloric restriction (75% over 14 h) prior to asphyxial cardiac arrest and resuscitation (CA) improves survival and neurological recovery as measured by, behavioral testing on neurological deficit scores, faster recovery of quantitative electroencephalography (EEG) burst suppression ratio, and complete prevention of neurodegeneration in multiple regions of the brain. We also show that overnight CR normalizes stress-induced hyperglycemia, while significantly decreasing insulin and glucagon production and increasing corticosterone and ketone body production. The benefits seen with ultra-short CR appear independent of Sirtuin 1 (SIRT-1) and brain-derived neurotrophic factor (BDNF) expression, which have been strongly linked to neuroprotective benefits seen in chronic CR. Mechanisms underlying neuroprotective effects remain to be defined, and may reveal targets for providing protection pre-CA or therapeutic interventions post-CA. These findings are also of high importance to basic sciences research as we demonstrate that minor, often-overlooked alterations to pre-experimental dietary procedures can significantly affect results, and by extension, research homogeneity and reproducibility, especially in acute ischemic brain injury models.
Highlights
For almost a century, caloric restriction (CR) has been shown to have a multitude of health benefits in both humans and animals (Heilbronn and Ravussin, 2003)
Surgical preparation for the cardiac arrest and resuscitation (CA) experiment resulted in control rats exhibiting stress-induced hyperglycemia, with glucose levels above normal
These results suggest that rats undergoing asphyxial CA display a stress-induced hyperglycemic response that is inhibited in entirety by 14 h of caloric restriction
Summary
Caloric restriction (CR) has been shown to have a multitude of health benefits in both humans and animals (Heilbronn and Ravussin, 2003). Several studies on CR have proposed to explain its cellular and molecular mechanisms of action on the brain, which involve a wide range of pathways, including metabolic, inflammatory, oxidative stress, and cellular regenerative mechanisms (Ungvari et al, 2008; Maalouf et al, 2009). These studies, have predominantly focused on long-term CR, which is clinically impractical for a variety of reasons, including issues of adherence and is irrelevant for treating brain injuries after they occur. Long-term CR seems to involve a multiplicity of cellular pathways, it appears that shortterm CR has far been linked to SIRT-1 and BDNF pathways, as several additional studies have pinpointed these downstream mechanisms, in models of traumatic brain injury and focal stroke (Duan et al, 2001; Zuccato and Cattaneo, 2009; She et al, 2017)
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