Abstract 21158: Ultra-Short Caloric Restriction Prior to Cardiac Arrest and Resuscitation Leads to Improved Survival and Neurological Outcome in a Rodent Model

Abstract

Introduction: Caloric restriction (CR) has been widely shown to have both cardioprotective and neuroprotective properties. However, nearly all studies have investigated chronic CR with mechanisms linked to the upregulation of SIRT-1 and BDNF. Minimal to no focus has been placed on the potential benefits of transient CR in models of brain injury, including stroke. Furthermore, the effects of transient CR in cardiac arrest-induced global cerebral ischemia have not been evaluated. We investigated the effects of overnight (~14-hour) CR on survival and neurological outcome in a rodent model of cardiac arrest (CA). Methods: Adult male Wistar rats (n=28) were divided into 75% CR (n=14) and non-CR (n=14) groups 14hrs prior to rats undergoing intubation, mechanical ventilation, cannulation of femoral vessels, and 8 minutes of asphyxial CA followed by cardiopulmonary resuscitation (CPR). Blood glucose was measured before CA. We conducted neurological deficit scale (NDS) behavioral testing at 4hrs, 24hrs, 48hrs, and 72hrs post-CA. The NDS score ranges from 0 (dead) to 80 (normal). Rats were euthanized after 72hrs and tissue was collected for protein analysis via Western blot. Results: CR, in comparison to no-CR, resulted in significant reduction of mortality (0% vs. 28.6%; Kaplan-Meier log-rank test, p< 0.05). Of those that survived, NDS scores improved significantly in the CR group at 4hrs (32.8±6.1 vs. 24.5±3.3; p<0.05), 24hrs (66.5±8.4 vs. 57.0±7.9; p< 0.05), 48hrs (73.1±4.7 vs. 61.3±12.5; p< 0.05), and 72hrs (76.3±3.3 vs. 73.14±12.2; p< 0.05). CR also significantly lowered pre-CA glucose levels (151.0±22.1 vs. 220.7±17.5; p< 0.05). Western blot analysis yielded no significant difference in BDNF and SIRT-1 expression in brain regions of CR vs. non-CR rats. Conclusions: Our results demonstrate that ultra-short CR (~14 hours) significantly improves survival and neurological outcome after CA/CPR. Interestingly, these improvements appear to be independent of BDNF or SIRT-1 pathways, commonly linked to chronic CR. While ultra-short CR improved glycemic control in rats, further investigation into the underlying molecular mechanisms are imperative to explore potential translational and therapeutic implications, including for patients at high risk of CA.