Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.

OLEANOLIC ACID, A PROSPECTIVE PROTECTIVE AGENT AGAINST BRAIN ENERGY METABOLISM AND OXIDATIVE DYSFUNCTIONS FOLLOWING HEXAVALENT CHROMIUM EXPOSURE IN MICE

Objective: Effect of oleanolic acid against hexavalent chromium-induced altered brain energy metabolism associated with oxidative stress was evaluated in the present study. Methods: Swiss albino mice were divided into three groups, Control (n=6), chromium-treated (n=6), and oleanolic acid (OA) supplemented (n=6). The chromium treated group was orally administered with K2Cr2O7 for 30 days at a dose of 10 mg/kg b.w/day. OA supplementation was given at a dose of 5 mg/kg bw/day for the past 14 days of chromium treatment. Control group received the vehicle only. After the treatment, whole brain was removed for examining the parameters such as pyruvic acid, free amino nitrogen, tissue protein, TCA cycle enzyme activities, NADH dehydrogenase function, and oxidative stress markers. Results: Significant decrease in cerebral pyruvic acid content associated with suppressed malate dehydrogenase and succinate dehydrogenase activities were observed. The NADH dehydrogenase activity was inhibited owing to enhanced accumulation of chromium in cerebral tissue. Depletion of proteins and increased free amino acid nitrogen were accompanied with inhibited cathepsin, pronase and trypsin activities, and increased transaminase function. In addition, GSH content was decreased along with increased lipid peroxidation, oxidized GSSG content, TG/GSSG ratio, carbonylated protein content, and tissue free hydroxyl radical formation. Superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase were also inhibited by hexavalent chromium. Oleanolic acid supplementation was found to have significant protective effect against brain metabolic and oxidative dysfunctions. Conclusion: The present study elucidated therapeutic efficacy of oleanolic acid against hexavalent chromium toxicity in brain tissue of mice.

Effects of Simultaneous Exposure to a Western Diet and Wheel-Running Training on Brain Energy Metabolism in Female Rats

Background: In the pathogenesis of central nervous system disorders (e.g., neurodegenerative), an important role is attributed to an unhealthy lifestyle affecting brain energy metabolism. Physical activity in the prevention and treatment of lifestyle-related diseases is getting increasing attention. Methods: We performed a series of assessments in adult female Long Evans rats subjected to 6 weeks of Western diet feeding and wheel-running training. A control group of lean rats was fed with a standard diet. In all experimental groups, we measured physiological parameters (animal weights, body composition, serum metabolic parameters). We assessed the impact of simultaneous exposure to a Western diet and wheel running on the cerebrocortical protein expression (global proteomic profiling), and in the second part of the experiment, we measured the cortical levels of protein related to brain metabolism (Western blot). Results: Western diet led to an obese phenotype and induced changes in the serum metabolic parameters. Wheel running did not reduce animal weights or fat mass but significantly decreased serum glucose level. The global proteome analysis revealed that the altered proteins were functionally annotated as they were involved mostly in metabolic pathways. Western blot analysis showed the downregulation of the mitochondrial protein—Acyl-CoA dehydrogenase family member 9, hexokinase 1 (HK1)—enzyme involved in principal glucose metabolism pathways and monocarboxylate transporter 2 (MCT2). Wheel running reversed this decline in the cortical levels of HK1 and MCT2. Conclusion: The cerebrocortical proteome is affected by a combination of physical activity and Western diet in female rats. An analysis of the cortical proteins involved in brain energy metabolism provides a valuable basis for the deeper investigation of changes in the brain structure and function induced by simultaneous exposure to a Western diet and physical activity.

Bibliometric Analysis Study on the Mechanisms of Brain Energy Metabolism Disorders in Alzheimer's Disease From 2000 to 2020

Alzheimer's disease (AD) is currently one of the main diseases afflicting the elderly in the world. In recent years, more and more studies have shown that brain energy metabolism disorders are the key pathogenic factors and main early pathological features of AD. Many risk factors such as insulin resistance, mitochondrial dysfunction, oxidative stress, Aβ-amyloid plaques, neurofibrillary tangles of hyperphosphorylated tau, aging, and neuroinflammation are involved in brain energy metabolism disorders. In this study, 1,379 Web of Science publications on the mechanisms of brain energy metabolism disorders in AD, all published from 2000 to 2020, were analyzed. Some network maps were drawn using CiteSpace and VOSviewer software which can be used to clarify research focus, forecast research frontiers and development trends, and provide different perspectives and characteristics in AD brain energy metabolism disorder mechanisms.

Brain Energy Metabolism in Two States of Mind Measured by Phosphorous Magnetic Resonance Spectroscopy

Introduction: Various functional neuroimaging studies help to better understand the changes in brain activity during meditation. The purpose of this study was to investigate how brain energy metabolism changes during focused attention meditation (FAM) state, measured by phosphorous magnetic resonance spectroscopy (31P-MRS).Methods:31P-MRS imaging was carried out in 27 participants after 7 weeks of FAM training. Metabolite ratios and the absolute values of metabolites were assessed after meditation training in two MRI measurements, by comparing effects in a FAM state with those in a distinct focused attention awake state during a backwards counting task.Results: The results showed decreased phosphocreatine/ATP (PCr/ATP), PCr/ inorganic phosphate (Pi), and intracellular pH values in the entire brain, but especially in basal ganglia, frontal lobes, and occipital lobes, and increased Pi/ATP ratio, cerebral Mg, and Pi absolute values were found in the same areas during FAM compared to the control focused attention awake state.Conclusions: Changes in the temporal areas and basal ganglia may be interpreted as a higher energetic state induced by meditation, whereas the frontal and occipital areas showed changes that may be related to a down-regulation in ATP turnover, energy state, and oxidative capacity.