Brain Energy Metabolism Research Articles

SLC2A1 variants cause late-onset epilepsy and the genetic-dependent stage feature

BackgroundThe SLC2A1 gene plays a vital role in brain energy metabolism. SLC2A1 variants have been reported to be associated with early-onset refractory seizures. This study aims to explore the association between the SLC2A1 gene and late-onset epilepsy.MethodsTrios-based whole-exome sequencing was performed on patients with epilepsy without acquired etiologies. The pathogenicity of the variants was assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsA total of 14 heterozygous SLC2A1 variants were identified in 16 unrelated families. The variants were evaluated as “pathogenic” or “likely pathogenic” according to the ACMG guidelines. Ten cases (62.5%) presented with infantile onset seizures and developmental delay/intellectual disability and were diagnosed with developmental and epileptic encephalopathy (DEE). The other six cases (37.5%) exhibited late-onset seizures and normal development. They were diagnosed with idiopathic partial epilepsy (n = 2) or idiopathic generalized epilepsy (n = 4). Further analysis showed that DEE-associated variants tended to cluster in the transmembrane region, whereas the mild epilepsy-associated variants tended to locate in regions outside the transmembrane region, suggesting a potential molecular sub-regional effect. A total of 15 cases had delayed diagnosis, with the longest delay being 22 years. The SLC2A1 expression stage, which is expressed at relatively high level throughout the whole life span, from the embryonic to adult stages with two peaks at approximately four and 14 years, is generally consistent with the seizure onset age. In addition, patients with early-onset age had variants that were potentially associated with severe damage, suggesting a potential correlation between the age of disease onset and the damaging effects of the variants.ConclusionsSLC2A1 variants are associated with late-onset epilepsy, which is consistent with the genetic-dependent stage feature of SLC2A1. Early genetic diagnosis is important for treatment of patients with SLC2A1 variants.

Simultaneous assessment of cerebral glucose and oxygen metabolism and perfusion in rats using interleaved deuterium (2H) and oxygen-17 (17O) MRS.

Cerebral glucose and oxygen metabolism and blood perfusion play key roles in neuroenergetics and oxidative phosphorylation to produce adenosine triphosphate (ATP) energy molecules in supporting cellular activity and brain function. Their impairments have been linked to numerous brain disorders. This study aimed to develop an in vivo magnetic resonance spectroscopy (MRS) method capable of simultaneously assessing and quantifying the major cerebral metabolic rates of glucose (CMRGlc) and oxygen (CMRO2) consumption, lactate formation (CMRLac), and tricarboxylic acid (TCA) cycle (VTCA); cerebral blood flow (CBF); and oxygen extraction fraction (OEF) via a single dynamic MRS measurement using an interleaved deuterium (2H) and oxygen-17 (17O) MRS approach. We introduced a single-loop multifrequency radio-frequency (RF) surface coil that can be used to acquire proton (1H) magnetic resonance imaging (MRI) or interleaved low-γ X-nuclei 2H and 17O MRS. By combining this RF coil with a modified MRS pulse sequence, 17O-isotope-labeled oxygen gas inhalation, and intravenous 2H-isotope-labeled glucose administration, we demonstrate for the first time the feasibility of simultaneously and quantitatively measuring six important physiological parameters, CMRGlc, CMRO2, CMRLac, VTCA, CBF, and OEF, in rat brains at 16.4T. The interleaved 2H-17O MRS technique should be readily adapted to image and study cerebral energy metabolism and perfusion in healthy and diseased brains.

Practical supplements for prevention and management of migraine attacks: a narrative review.

Migraine is one of the most debilitating neurological disorders that causes frequent attacks of headaches and affects approximately 11% of the global population. Deficient or even insufficient levels of vital nutrients would increase the severity and frequency of migraine attacks. Therefore, we aimed to examine the practical supplements for the prevention and management of migraine attacks. This narrative review study was conducted by searching PubMed, ISI web of science, EMBASE, Google Scholar, and Scopus using the keywords of "dietary supplement" and "migraine" plus their MeSH terms. Original articles published in English language from their inception to July 27th, 2024, studies that investigated adult population (aged >18 years), and those assessing the impact of intended nutrient supplementation on clinical symptoms of migraine were included in the study. Oxidative stress and low intake of antioxidants would be risk factors for migraine attacks by inducing inflammation. The secretion of inflammatory cytokines, such as tumor necrosis factor (TNF)-a, would lead to neuroinflammation and migraine episodes by increasing the cellular permeability and interactions. Evidence also indicated a direct association between phases of migraine attacks and calcitonin gene-related peptide (CGRP), mitochondrial disorders, monoaminergic pathway, disruption in brain energy metabolism, and higher serum levels of glutamate and homocysteine. Therefore, supplementation with nutrients involved in mitochondrial function, brain energy metabolism, and even methyl donors would relieve migraine attacks. Evidence indicated that supplementation with riboflavin, omega-3 fatty acids, alpha lipoic acid, magnesium, probiotics, coenzyme Q10, ginger, and caffeine would have favorable effects on migraine patients. However, more prospective studies are required to evaluate the effect of other nutrients on migraine patients.

Role of glia in delirium: proposed mechanisms and translational implications.

Delirium is a common acute onset neurological syndrome characterised by transient fluctuations in cognition. It affects over 20% of medical inpatients and 50% of those critically ill. Delirium is associated with morbidity and mortality, causes distress to patients and carers, and has significant socioeconomic costs in ageing populations. Despite its clinical significance, the pathophysiology of delirium is understudied, and many underlying cellular mechanisms remain unknown. There are currently no effective pharmacological treatments which directly target underlying disease processes. Although many studies focus on neuronal dysfunction in delirium, glial cells, primarily astrocytes, microglia, and oligodendrocytes, and their associated systems, are increasingly implicated in delirium pathophysiology. In this review, we discuss current evidence which implicates glial cells in delirium, including biomarker studies, post-mortem tissue analyses and pre-clinical models. In particular, we focus on how astrocyte pathology, including aberrant brain energy metabolism and glymphatic dysfunction, reactive microglia, blood-brain barrier impairment, and white matter changes may contribute to the pathogenesis of delirium. We also outline limitations in this body of work and the unique challenges faced in identifying causative mechanisms in delirium. Finally, we discuss how established neuroimaging and single-cell techniques may provide further mechanistic insight at pre-clinical and clinical levels.

Brain Metabolism in Health and Neurodegeneration: The Interplay Among Neurons and Astrocytes.

The regulation of energy in the brain has garnered substantial attention in recent years due to its significant implications in various disorders and aging. The brain's energy metabolism is a dynamic and tightly regulated network that balances energy demand and supply by engaging complementary molecular pathways. The crosstalk among these pathways enables the system to switch its preferred fuel source based on substrate availability, activity levels, and cell state-related factors such as redox balance. Brain energy production relies on multi-cellular cooperation and is continuously supplied by fuel from the blood due to limited internal energy stores. Astrocytes, which interface with neurons and blood vessels, play a crucial role in coordinating the brain's metabolic activity, and their dysfunction can have detrimental effects on brain health. This review characterizes the major energy substrates (glucose, lactate, glycogen, ketones and lipids) in astrocyte metabolism and their role in brain health, focusing on recent developments in the field.

Brain hypoxia and metabolic crisis are common in patients with acute brain injury despite a normal intracranial pressure

Patients with acute brain injury are vulnerable to secondary deterioration, which may go undetected by traditional monitoring. However, multimodal neuromonitoring of brain tissue oxygen tension (PbtO2) and energy metabolism may be able to detect such episodes. We report a retrospective, observational study of 94 patients with aneurysmal subarachnoid haemorrhage (SAH) or traumatic brain injury (TBI) who underwent multimodal neuromonitoring during admission. We examined the co-occurrence of pathological neuromonitoring values: elevated intracranial pressure (ICP, > 20 mmHg), inadequate cerebral perfusion pressure (CPP, < 60 mmHg), brain hypoxia (PbtO2 < 20 mmHg), and metabolic crisis (lactate/pyruvate ratio > 40 and a glucose level < 0.2 mmol/L in cerebral microdialysate). Mixed effects linear regression demonstrated significant associations between abnormal ICP/CPP, cerebral hypoxia and metabolic crisis. However, brain hypoxia occurred in 40% and 31% of observations in patients with SAH and TBI, respectively, despite normal concurrent values of ICP. Similarly, metabolic crisis was observed in 8% and 16% of measurements for SAH and TBI, respectively, despite a normal ICP. The pattern was identical for CPP. In conclusion, although all neuromonitoring variables are interrelated, brain hypoxia and metabolic crisis are common despite an absence of abnormalities in conventional monitoring. Multimodal neuromonitoring may help identify such episodes and guide individualised treatment.

Methionine restriction alleviates diabetes-associated cognitive impairment via activation of FGF21

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.

Middle-aged dogs with low and high Aβ CSF concentrations show differences in energy and stress related metabolic profiles in CSF

BackgroundAmyloid beta (Aβ) accumulation in the brain is one of the earliest findings in Alzheimer's disease (AD). The dog is a natural animal model for amyloid processing and early brain amyloid pathology. The goal of this study is to examine which differences in metabolomic profiles in cerebrospinal fluid (CSF) could be detected in dogs with a difference in CSF Aβ concentrations before amyloid accumulation occurs. MethodMetabolic profiling was performed on CSF from 4 to 8 year old dogs with different CSF Aβ concentrations. ResultsMetabolomic profiling of CSF showed differences in brain energy metabolism. More specifically, increases in N-acetylation of amino acids and amino sugars, creatine and pentose metabolism, and a decrease in tricarboxylic acid (TCA) cycle were seen in dogs with a high CSF Aβ concentration. In addition, signs of elevated oxidative stress, higher methionine, lipid and nucleotide metabolism and increased levels of cysteine, myo-inositol and trimethylamine N-oxide were noted in these animals. ConclusionsDifferences in energy metabolism and stress mediated metabolic changes are seen in the brain of dogs with different CSF Aβ concentrations, before any amyloid deposition occurs. Similar metabolic changes, as in the high Aβ dogs, have been described in AD in humans and/or transgenic AD mice, some of them in very early phases. General significanceThe differences observed in metabolomic profiles could help in identifying potential biomarkers for an increased risk of developing amyloid pathology in the brain and open the door to the evaluation of preventive treatments for amyloid pathology in humans.

Brain energy metabolism as an underlying basis of slow and fast cognitive phenotypes in honeybees.

In the context of slow-fast behavioral variation, fast individuals are hypothesized to be those who prioritize speed over accuracy while slow individuals are those which do the opposite. Since energy metabolism is a critical component of neural and cognitive functioning, this predicts such differences in cognitive style to be reflected at the level of the brain. We tested this idea in honeybees by first classifying individuals into slow and fast cognitive phenotypes based on a learning assay and then measuring their brain respiration with high-resolution respirometry. Our results broadly show that inter-individual differences in cognition are reflected in differences in brain mass and accompanying energy use at the level of the brain and the whole animal. Larger brains had lower mass-specific energy usage and bees with larger brains had a higher metabolic rate. These differences in brain respiration and brain mass were, in turn, associated with cognitive differences, such that bees with larger brains were fast cognitive phenotypes whereas those with smaller brains were slow cognitive phenotypes. We discuss these results in the context of the role of energy in brain functioning and slow-fast decision making and speed accuracy trade-off.

A tribute to Arne Schousboe's contributions to neurochemistry and his innovative and enduring research in GABA, glutamate, and brain energy metabolism.

This is a tribute to Arne Schousboe, Professor Emeritus at the University of Copenhagen, an eminent neurochemist and neuroscientist who was a leader in the fields of GABA, glutamate, and brain energy metabolism. Arne was known for his keen intellect, his wide-ranging expertise in neurochemistry and neuropharmacology of GABA and glutamate and brain energy metabolism. Arne was also known for his strong leadership, his warm and engaging personality and his enjoyment of fine wine and great food shared with friends, family, and colleagues. Sadly, Arne passed away on February 27, 2024, after a short illness. He is survived by his wife Inger Schousboe, his two children, and three wonderful grandchildren. His death is a tremendous loss to the neuroscience community. He will be greatly missed by his friends, family, and colleagues. Some of the highlights of Arne's career are described in this tribute.

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer's disease.

Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well-known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock-in (APPSAA) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. NiMA is inhibited in APPSAA mice before other defects are detected in these Aβ-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA mice, and may represent an early stage in human AD. Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient-induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock-in (APPSAA/+) mice. NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo.

Modulation of brain energy metabolism in hepatic encephalopathy: impact of glucose metabolic dysfunction.

Cerebral function is linked to a high level of metabolic activity and relies on glucose as its primary energy source. Glucose aids in the maintenance of physiological brain activities; as a result, a disruption in metabolism has a significant impact on brain function, launching a chain of events that leads to neuronal death. This metabolic insufficiency has been observed in a variety of brain diseases and neuroexcitotoxicity disorders, including hepatic encephalopathy. It is a significant neurological complication that develops in people with liver disease, ranging from asymptomatic abnormalities to coma. Hyperammonemia is the main neurotoxic villain in the development of hepatic encephalopathy and induces a wide range of complications in the brain. The neurotoxic effects of ammonia on brain function are thought to be mediated by impaired glucose metabolism. Accordingly, in this review, we provide an understanding of deranged brain energy metabolism, emphasizing the role of glucose metabolic dysfunction in the pathogenesis of hepatic encephalopathy. We also highlighted the differential metabolic profiles of brain cells and the status of metabolic cooperation between them. The major metabolic pathways that have been explored are glycolysis, glycogen metabolism, lactate metabolism, the pentose phosphate pathway, and the Krebs cycle. Furthermore, the lack of efficacy in current hepatic encephalopathy treatment methods highlights the need to investigate potential therapeutic targets for hepatic encephalopathy, with regulating deficient bioenergetics being a viable alternative in this case. This review also demonstrates the importance of the development of glucose metabolism-focused disease diagnostics and treatments, which are now being pursued for many ailments.

Hominis Placenta modulates PTSD-like behaviors in SPSS-induced PTSD mice: Regulating energy metabolism and neuronal activity

The symptoms of post-traumatic stress disorder (PTSD) include re-experiencing trauma, avoidance behaviors, negative alterations in cognition and mood. However, the underlying molecular mechanisms are unclear. Dysfunction of hypothalamic-pituitary-adrenal axis (HPA-axis) and dysregulation of glutamatergic and GABAergic systems were shown during PTSD. Therefore, regulating hormonal change or glutamate energy metabolism are considered as a therapeutic approach to alleviate this condition. Herbal medicine may be effective in treating PTSD due to its ability to target multiple underlying mechanisms with various compounds. Hominis placenta (HP) is a traditional medicine widely used in East Asia for various conditions. However, the effect on PTSD has not been clarified. We aimed to investigate the effects of HP treatment in single-prolonged stress with shock (SPSS)-induced PTSD mice and explore its possible mechanisms. HP treatment at ST36 acupoints, combined with herbal medicine and acupuncture point stimulation, was applied three times/week for 2 weeks. HP treatment effectively alleviated anxiety and cognitive decline in SPSS-induced PTSD mice, as detected by Open field and the Y-maze test. Additionally, HP decreased the corticosterone levels and proinflammatory cytokines in the serum, modulated brain energy metabolism, and inhibited glutamate excitotoxicity, while regulating neuronal activity through modulating brain-derived neurotrophic factor (BDNF) levels, as demonstrated by western blot and immunohistochemistry, and flow cytometry analyses. These findings reveal that HP treatment effectively alleviates PTSD-like behaviors by regulating energy metabolism and neuronal activity though modulation of the HPA-axis and BDNF levels in PTSD mice, indicating that HP treatment is a promising therapeutic approach for PTSD.

Utility of melatonin on brain injury, synaptic transmission, and energy metabolism in rats with sepsis.

Melatonin is a powerful endogenous antioxidant hormone. Its healing effects on energy balance and neuronal damage associated with oxidative metabolism disorders have been reported in pathologic conditions. We aimed to determinate the utility of melatonin on neuronal damage, synaptic transmission, and energy balance in the brain tissue of rats with sepsis induced with LPS. Rats was divided into four groups such as control, LPS (20mg/kg i.p.), melatonin (10mg/kg i.p. × 3), and LPS + Melatonin (LPS + Mel). After 6h from the first injection, rats were decapitated, and also tissue and serum samples were taken. Lipid peroxidation and neuron-specific enolase (NSE) levels were determined from the serum in all group. High energy compounds, creatine, and creatine phosphate are measured by HPLC methods from the homogenized tissue. Counts of living neurons are marked with NeuN (neuronal nuclei), degenerated neurons are marked with S100-ß and synaptic vesicles transmission is analyzed with synaptophysin antibodies immunoreactivities. One-way ANOVA and post hoc Tukey tests were used to statistical analysis. In LPS group, AMP, ATP, creatine, and creatine phosphate levels were significantly decreased (p < 0.05), and also ADP levels were significantly increased compared with the other groups (p < 0.01). Living neurons counts were significantly decreased in LPS (p < 0.01), melatonin, and LPS + Melatonin (p < 0.05) groups compared with control. Degenerated neurons counts were increased in LPS group compared with control (p < 0.01) and also decreased in both of melatonin and LPS + Melatonin groups (p < 0.01). Synaptophysin immunoreactivity was decreased in LPS group compared with the other groups (p < 0.05). We observed that melatonin administration prevents neuronal damage, regulates energy metabolism, and protects synaptic vesicle proteins from sepsis-induced reduction.

CREB-regulated transcription during glycogen synthesis in astrocytes

Glycogen storage, conversion and utilization in astrocytes play an important role in brain energy metabolism. The conversion of glycogen to lactate through glycolysis occurs through the coordinated activities of various enzymes and inhibition of this process can impair different brain processes including formation of long-lasting memories. To replenish depleted glycogen stores, astrocytes undergo glycogen synthesis, a cellular process that has been shown to require transcription and translation during specific stimulation paradigms. However, the detail nuclear signaling mechanisms and transcriptional regulation during glycogen synthesis in astrocytes remains to be explored. In this report, we study the molecular mechanisms of vasoactive intestinal peptide (VIP)-induced glycogen synthesis in astrocytes. VIP is a potent neuropeptide that triggers glycogenolysis followed by glycogen synthesis in astrocytes. We show evidence that VIP-induced glycogen synthesis requires CREB-mediated transcription that is calcium dependent and requires conventional Protein Kinase C but not Protein Kinase A. In parallel to CREB activation, we demonstrate that VIP also triggers nuclear accumulation of the CREB coactivator CRTC2 in astrocytic nuclei. Transcriptome profiles of VIP-induced astrocytes identified robust CREB transcription, including a subset of genes linked to glucose and glycogen metabolism. Finally, we demonstrate that VIP-induced glycogen synthesis shares similar as well as distinct molecular signatures with glucose-induced glycogen synthesis, including the requirement of CREB-mediated transcription. Overall, our data demonstrates the importance of CREB-mediated transcription in astrocytes during stimulus-driven glycogenesis.

Impaired energy metabolism and altered brain histoarchitecture characterized by inhibition of glycolysis and mitochondrial electron transport-linked enzymes in rats exposed to diisononyl phthalate

The brain is an energy demanding organ, constituting about 20 % of the body's resting metabolic rate. An efficient energy metabolism is critical to neuronal functions. Glucose serves as the primary essential energy source for the adult brain and plays a critical role in supporting neural growth and development. Endocrine disrupting chemicals (EDCs) such as phthalates has been shown to have a negative impact on neurological functions. The impact of diisononyl phthalate (DiNP) on neural energy transduction using cellular energy metabolizing enzymes as indicators was examined. Over the course of 14 days, eighteen (18) albino rats divided into three groups (1,2 and 3) of six albino rats were given Tween-80/saline, 20 and 200 mg/kg body weight respectively. In the brain, we assessed histological changes as well as activities of selected enzymes of energy metabolism such as the glycolytic pathway, citric acid cycle and mitochondrial electron transport-linked complexes. Activities of the glycolytic and TCA cycle enzymes assayed were significantly decreased except citrate synthase activity with no statistically significant change following the administration of DiNP. Also, respiratory chain complexes (Complex I-IV) activities were significantly reduced when compared to control. DiNP exposure altered the histological integrity of various brain sections. These include degenerated Purkinje neurons, distortion of the granular layer and Purkinje cell layer. Data from this study indicated impaired brain energy metabolism via down-regulation of enzymes of cellular respiration of the glycolytic and oxidative phosphorylation pathways and altered brain histoarchitecture orchestrated by DiNP exposure.

Preliminary Observations of the Loke Microdialysis in an Experimental Pig Model: Are We Ready for Continuous Monitoring of Brain Energy Metabolism?

Brain energy metabolism is often disturbed after acute brain injuries. Current neuromonitoring methods with cerebral microdialysis (CMD) are based on intermittent measurements (1-4 times/h), but such a low frequency could miss transient but important events. The solution may be the recently developed Loke microdialysis (MD), which provides high-frequency data of glucose and lactate. Before clinical implementation, the reliability and stability of Loke remain to be determined in vivo. The purpose of this study was to validate Loke MD in relation to the standard intermittent CMD method. Four pigs aged 2-3 months were included. They received two adjacent CMD catheters, one for standard intermittent assessments and one for continuous (Loke MD) assessments of glucose and lactate. The standard CMD was measured every 15 min. Continuous Loke MD was sampled every 2-3 s and was averaged over corresponding 15-min intervals for the statistical comparisons with standard CMD. Intravenous glucose injections and intracranial hypertension by inflation of an intracranial epidural balloon were performed to induce variations in intracranial pressure, cerebral perfusion pressure, and systemic and cerebral glucose and lactate levels. In a linear mixed-effect model of standard CMD glucose(mM), there was a fixed effect value (± standard error [SE]) at 0.94 ± 0.07 (p < 0.001) for Loke MD glucose(mM), with an intercept at - 0.19 ± 0.15 (p = 0.20). The model showed a conditional R2 at 0.81 and a marginal R2 at 0.72. In a linear mixed-effect model of standard CMD lactate(mM), there was a fixed effect value (± SE) at 0.41 ± 0.16 (p = 0.01) for Loke MD lactate(mM), with an intercept at 0.33 ± 0.21 (p = 0.25). The model showed a conditional R2 at 0.47 and marginal R2 at 0.17. The established standard CMD glucose thresholds may be used as for Loke MD with some caution, but this should be avoided for lactate.

Metabolic Insights into Neuropsychiatric Illnesses and Ketogenic Therapies: A Transcriptomic View.

The disruption of brain energy metabolism, leading to alterations in synaptic signaling, neural circuitry, and neuroplasticity, has been implicated in severe mental illnesses such as schizophrenia, bipolar disorder, and major depressive disorder. The therapeutic potential of ketogenic interventions in these disorders suggests a link between metabolic disturbances and disease pathology; however, the precise mechanisms underlying these metabolic disturbances, and the therapeutic effects of metabolic ketogenic therapy, remain poorly understood. In this study, we conducted an in silico analysis of transcriptomic data to investigate perturbations in metabolic pathways in the brain across severe mental illnesses via gene expression profiling. We also examined dysregulation of the same pathways in rodent or cell culture models of ketosis, comparing these expression profiles to those observed in the disease states. Our analysis revealed significant perturbations across all metabolic pathways, with the greatest perturbations in glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC) across all three disorders. Additionally, we observed some discordant gene expression patterns between disease states and ketogenic intervention studies, suggesting a potential role for ketone bodies in modulating pathogenic metabolic changes. Our findings highlight the importance of understanding metabolic dysregulation in severe mental illnesses and the potential therapeutic benefits of ketogenic interventions in restoring metabolic homeostasis. This study provides insights into the complex relationship between metabolism and neuropsychiatric disorders and lays the foundation for further experimental investigations aimed at appreciating the implications of the present transcriptomic findings as well as developing targeted therapeutic strategies.

A Comprehensive Review on Hepatic Encephalopathy: Pathophysiology, Symptoms, Epidemiology, Classification, Diagnosis and Treatment

The condition known as hepatic encephalopathy (HE) is a state of impaired brain function that can be reversed and is experienced by patients who are suffering from severe liver diseases. Neurotoxins, decreased neurotransmission as a result of metabolic anomalies in liver failure, changes in brain energy metabolism, systemic inflammatory response, and alterations of the blood brain barrier are the primary hypotheses that are still being explored in relation to the precise pathophysiology of hepatic encephalopathy (HE). There is a wide spectrum of severity regarding the neurological and mental symptoms that can be brought on by HE. For the purpose of diagnosing limited HE, abnormal psychometric tests are utilised. Alterations in personality, altered states of consciousness, gradual spatial and temporal disorientation, lethargy, stupor, and coma are some of the characteristics of HE that are clinically noticeable. For the purpose of diagnosis, specific testing is not required outside of clinical studies. HE is classified according to the underlying disease, the severity of symptoms, the length of time it has been present, and whether or not there are triggers that cause it to occur. Hepatic encephalopathy refers to a collection of neuropsychiatric illnesses that can be treated and are characterised by the presence of symptoms in individuals who have liver disease or who have undergone portosystemic shunting. Entephalopathy, a disabling result of cirrhosis, affects thirty-five percent to forty-five percent of cirrhotic patients. Before recently, the treatment choices for HE that were available in hospitals were depending on anecdotal evidence, the availability of medication, and the norms of the relevant institutions. An increasing number of randomised controlled trials (RCTs) are providing further confirmation of the central significance of the basic HE therapy techniques (lactulose, branched-chain amino acids, and rifaximin), as well as the rising body of evidence showing the large beneficial advantages associated with these strategies. The liver transplantation and embolisation of large PSSs are two treatments that have proven to be effective for a select group of patients who have been carefully selected. Not only does it have a significant influence on the day-to-day lives of patients and carers, but it is also associated with increased rates of sickness and death and consumes a significant amount of resources in the healthcare system. In this article, we examine the history of hepatic encephalopathy, as well as the current understanding of the condition and the potential treatments for it.

Adenosine signalling to astrocytes coordinates brain metabolism and function

Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood5,6. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3′,5′-monophosphate–protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.