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The role of Sirtuins in brain function is emerging, yet little is known about SIRT5 in this domain. Our previous work demonstrates that protein kinase C epsilon (PKCε)-induced protection from focal ischemia is lost in SIRT5 mice. Thus, metabolic regulation by SIRT5 contributes significantly to ischemic tolerance. The aim of this study was to identify the SIRT5-regulated metabolic pathways in the brain and determine which of those pathways are linked to PKCε. Our results show SIRT5 is primarily expressed in neurons and endothelial cells in the brain, with mitochondrial and extra-mitochondrial localization. Pathway and enrichment analysis of non-targeted primary metabolite profiles from Sirt5 cortex revealed alterations in several pathways including purine metabolism (urea, adenosine, adenine, xanthine), nitrogen metabolism (glutamic acid, glycine), and malate-aspartate shuttle (malic acid, glutamic acid). Additionally, perturbations in β-oxidation and carnitine transferase (pentadecanoic acid, heptadecanoic acid) and glutamate transport and glutamine synthetase (urea, xylitol, adenine, adenosine, glycine, glutamic acid) were predicted. Metabolite changes in SIRT5 coincided with alterations in expression of amino acid (SLC7A5, SLC7A7) and glutamate (EAAT2) transport proteins as well as key enzymes in purine (PRPS1, PPAT), fatty acid (ACADS, HADHB), glutamine-glutamate (GAD1, GLUD1), and malate-aspartate shuttle (MDH1) metabolic pathways. Moreover, PKCε activation induced alternations in purine metabolites (urea, glutamine) that overlapped with putative SIRT5 pathways in WT but not in SIRT5 mice. Finally, we found that purine metabolism is a common metabolic pathway regulated by SIRT5, PKCε and ischemic preconditioning. These results implicate Sirt5 in the regulation of pathways central to brain metabolism, with links to ischemic tolerance.

Aims Exposure to recurrent hypoglycemia (RH) is common in diabetic patients receiving glucose‐lowering therapies and is implicated in causing cognitive impairments. Despite the significant effect of RH on hippocampal function, the underlying mechanisms are currently unknown. Our goal was to determine the effect of RH exposure on hippocampal metabolism in treated streptozotocin‐diabetic rats. Methods Hyperglycemia was corrected by insulin pellet implantation. Insulin‐treated diabetic (ITD) rats were exposed to mild/moderate RH once a day for 5 consecutive days. Results The effect of RH on hippocampal metabolism revealed 65 significantly altered metabolites in the RH group compared with controls. Several significant differences in metabolite levels belonging to major pathways (eg, Krebs cycle, gluconeogenesis, and amino acid metabolism) were discovered in RH‐exposed ITD rats when compared to a control group. Key glycolytic enzymes including hexokinase, phosphofructokinase, and pyruvate kinase were affected by RH exposure. Conclusion Our results demonstrate that the exposure to RH leads to metabolomics alterations in the hippocampus of insulin‐treated streptozotocin‐diabetic rats. Understanding how RH affects hippocampal metabolism may help attenuate the adverse effects of RH on hippocampal functions.

Background Resting-state electroencephalography (rsEEG) is usually obtained to assess seizures in comatose patients with traumatic brain injury (TBI). We aim to investigate rsEEG measures and their prediction of early recovery of consciousness in patients with TBI. Methods This is a retrospective study of comatose patients with TBI who were admitted to a trauma center (October 2013 to January 2022). Demographics, basic clinical data, imaging characteristics, and EEGs were collected. We calculated the following using 10-min rsEEGs: power spectral density, permutation entropy (complexity measure), weighted symbolic mutual information (wSMI, global information sharing measure), Kolmogorov complexity (Kolcom, complexity measure), and heart-evoked potentials (the averaged EEG signal relative to the corresponding QRS complex on electrocardiography). We evaluated the prediction of consciousness recovery before hospital discharge using clinical, imaging, and rsEEG data via a support vector machine. Results We studied 113 of 134 (84%) patients with rsEEGs. A total of 73 (65%) patients recovered consciousness before discharge. Patients who recovered consciousness were younger (40 vs. 50 years, p  = 0.01). Patients who recovered also had higher Kolcom ( U  = 1688, p  = 0.01), increased beta power ( U  = 1,652 p  = 0.003) with higher variability across channels ( U  = 1534, p  = 0.034) and epochs ( U  = 1711, p  = 0.004), lower delta power ( U  = 981, p  = 0.04), and higher connectivity across time and channels as measured by wSMI in the theta band ( U  = 1636, p  = 0.026; U  = 1639, p  = 0.024) than those who did not recover. The area under the receiver operating characteristic curve for rsEEG was higher than that for clinical data (using age, motor response, pupil reactivity) and higher than that for the Marshall computed tomography classification (0.69 vs. 0.66 vs. 0.56, respectively; p  < 0.001). Conclusions We describe the rsEEG signature in recovery of consciousness prior to discharge in comatose patients with TBI. rsEEG measures performed modestly better than the clinical and imaging data in predicting recovery.

Cardiac arrest effects over half a million people in the United States annually. A lack of brain perfusion results in a global brain ischemia resulting in cell death in several regions including the hippocampus, an area important for learning and memory. Nearly half the survivors of cardiac arrest suffer from cognitive deficits. While there remains no well accepted therapy for these patients, it has been shown that exercise after focal brain ischemia (i.e. stroke) enhances both motor and cognitive function. But this has never been explored in the setting of cardiac arrest. In this study, we determined that a brief period of exercise of sufficient intensity enhances contextual but not spatial memory after cardiac arrest. This improvement was not due to acute effects of exercise as contextual memory was tested over a week after the last exercise session. Additionally, the enhancement in contextual memory was not correlated to enhanced hippocampal BDNF signaling despite increased BDNF protein levels in exercised animals. Likewise, there was no increase in neuronal proliferation in the dentate gyrus in exercised animals. Neuroprotection was not increased with exercise after cardiac arrest and exercise may enhance cell death after cardiac arrest. Further studies are needed to ascertain the mechanism of exercise- mediated enhancement of contextual memory after cardiac arrest.