Search Results (104)

Background: Neonatal hypoxic–ischemic encephalopathy remains a leading cause of neonatal mortality and long-term neurodevelopmental disability worldwide. Despite the widespread adoption of therapeutic hypothermia, a substantial proportion of affected infants experience death or significant neurological impairment. Given their metabolic vulnerability, ketogenic diet strategies and ketone bodies have emerged as potential adjunctive neuroprotective interventions. This scoping review aims to critically evaluate the mechanistic rationale, preclinical evidence, and clinical feasibility of ketogenic approaches. Methods: A scoping review of the literature was conducted, including experimental and clinical studies investigating ketogenic diets, endogenous ketosis, and exogenous ketone supplementation in neonatal hypoxia–ischemia. Evidence was synthesized across mechanistic, preclinical, nutritional, and clinical domains, with particular attention to developmental context, timing of intervention, safety considerations, and translational relevance in the contest of therapeutic hypothermia. Results: Preclinical studies consistently demonstrate that ketone bodies enhance cerebral energy metabolism, support mitochondrial function, reduce excitotoxic signaling, and attenuate oxidative stress and neuroinflammation in the immature brain. Neonatal models show preferential utilization of β-hydroxybutyrate over glucose during hypoxic–ischemic stress, suggesting intrinsic metabolic advantages. Emerging evidence also supports potential long-term effects on epigenetic regulation and white matter development, although direct causal validation in neonatal HIE remains limited. Nutritional studies indicate that carefully monitored enteral and parenteral feeding is feasible in critically ill neonates, identifying a potential window for metabolic interventions. Conclusions: Ketogenic strategies represent a plausible, multimodal approach to targeting the metabolic and inflammatory sequelae of neonatal HIE. While current evidence is insufficient to support clinical implementation, this scoping review provides a hypothesis-generating framework to guide future translational research and the design of carefully controlled clinical trials in neonatal neurocritical care. Full article

Obesity is a systemic metabolic disorder characterized by chronic low-grade inflammation and insulin resistance, with growing evidence indicating that the brain represents a primary and particularly vulnerable target organ. Beyond peripheral metabolic consequences, obesity induces region-specific structural, functional, and biochemical alterations within the central nervous system, contributing to cognitive impairment, dysregulated energy homeostasis, and increased susceptibility to neurodegenerative diseases. This narrative review examines key neurometabolic and neuroinflammatory mechanisms underlying obesity-related brain vulnerability, including downstream neuroinflammation, impaired insulin signaling, mitochondrial dysfunction, oxidative stress, blood–brain barrier disruption, and impaired brain clearance mechanisms. These processes preferentially affect frontal and limbic networks involved in executive control, reward processing, salience detection, and appetite regulation. Advanced neuroimaging has substantially refined our understanding of these mechanisms. Magnetic resonance spectroscopy provides unique in vivo insight into early neurometabolic alterations that may precede irreversible structural damage and is complemented by diffusion imaging, volumetric MRI, functional MRI, cerebral perfusion imaging, and positron emission tomography. Together, these complementary modalities reveal microstructural, network-level, structural, hemodynamic, and molecular alterations associated with obesity-related brain vulnerability and support the concept that such brain dysfunction is dynamic and potentially modifiable. Integrating neurometabolic and multimodal neuroimaging biomarkers with metabolic and clinical profiling may improve early risk stratification and guide preventive and therapeutic strategies aimed at preserving long-term brain health in obesity. Full article

Type 2 Diabetes Mellitus (T2DM) is a recognized risk factor for Alzheimer’s Disease (AD), as epidemiological research indicates that those with T2DM have a markedly increased risk of experiencing cognitive decline and dementia. Chronic hyperglycemia and insulin resistance in T2DM hinder cerebral glucose metabolism, reducing the primary energy source for neurons and compromising synaptic function. Insulin resistance impairs signaling pathways crucial for neuronal survival and plasticity, while high insulin levels compete with amyloid-β (Aβ) for breakdown by insulin-degrading enzyme, promoting Aβ buildup. Additionally, vascular issues linked to T2DM impair blood–brain barrier functionality, decrease cerebral blood flow, and worsen neuroinflammation. Elevated oxidative stress and advanced glycation end-products (AGEs) in diabetes exacerbate tau hyperphosphorylation and mitochondrial dysfunction, worsening neurodegeneration. Collectively, these processes create a robust biological connection between T2DM and AD, emphasizing the significance of metabolic regulation as a possible treatment approach for preventing or reducing cognitive decline. Here, we review the relationship between T2DM and AD and discuss the roles insulin, hyperglycemia, and inflammation therapeutic strategies have in successful development of AD therapies. Additionally evaluated are recent therapeutic advances, especially involving the polyflavonoid anthocyanin, against T2DM-mediated AD pathology. Full article

Lactate, as a pivotal metabolite generated by the body, has attracted considerable attention in numerous biological disciplines in recent years. In addition to its role in supplying energy, lactate also functions as a signaling molecule, with the capacity to mediate a diverse array of physiological effects. Within the central nervous system, lactate is involved in the regulation of critical physiological processes, including neurogenesis, synaptic plasticity, mitochondrial biogenesis, neuroinflammation, and cerebral angiogenesis. Furthermore, lactate has been implicated in the pathogenesis of several central nervous system diseases, such as Alzheimer’s disease, stroke, and spinal cord injury, among others. Physical exercise is recognized as a significant neuroprotective strategy; however, further research is required to elucidate the underlying biological mechanisms. In essence, the role of lactate as a metabolic-epigenetic core is gradually becoming a subject of increasing academic interest. The regulatory function of lactate is thought to involve its production (via lactate dehydrogenase), shuttle (via monocarboxylate transporters), sensing (via G protein-coupled receptor 81), and lactylation modifications, among others. This review synthesizes current evidence to elucidate the multifaceted roles of lactate in central nervous system physiology and pathology under exercise regulation, with a view to bridging the gap between molecular mechanisms and therapeutic potential, thereby paving the way for novel strategies in central nervous system disease intervention. Full article

Alzheimer’s disease (AD) is increasingly recognized as a disorder of cerebral energy metabolism, where impaired glucose utilization contributes to disease pathology. Medium-chain fatty acids (MCFAs), such as decanoic acid (C10), have emerged as promising metabolic substrates due to their ability to bypass glycolytic deficits and support mitochondrial function. In this study, we investigated the metabolic impact of C10 in the 5xFAD mouse model of AD and in human induced pluripotent stem cell (hiPSC)-derived astrocytes carrying familial AD mutations. Utilizing stable ¹³C-labeled metabolic tracers, we demonstrated that while [U-¹³C]glucose metabolism was largely preserved in cortical slices of 6-month-old 5xFAD female mice, [1,2-¹³C]acetate uptake was significantly reduced, suggesting impaired astrocytic metabolism. [U-¹³C]C10 was efficiently metabolized in both WT and 5xFAD brain slices, particularly in astrocytes, as indicated by high labeling of glutamine and citrate. Furthermore, C10 competitively inhibited glucose and acetate metabolism, suggesting its potential as an auxiliary energy substrate. In hiPSC-derived astrocytes, AD-specific metabolic responses to C10 varied by mutation, with only partial alterations in oxidative glucose metabolism observed in APP and PSEN1 variants, highlighting genotype-dependent metabolic alterations. While AD-related mutations in the hiPSC models did not lead to robust deficits, the in vivo environment in the 5xFAD model is associated with measurable metabolic changes in astrocytes. These findings underscore astrocytic metabolic dysfunction in AD and suggest that C10 supplementation may restore brain energy by supporting astrocytic oxidative metabolism. Full article

Background: Compared with normal weight, obese individuals display a variety of deviant measures in neuroenergetic status, food intake behavior, glucose metabolism, and circulating vitamin C levels. A chronically lowered neuroenergetic content is associated with increased food intake and disturbed glucose metabolism in obesity. In turn, a vitamin C deficiency found in obesity may be connected to these disturbances. Therefore, we investigated the effects of vitamin C application in the human brain. Methods: We intranasally applied vitamin C (80 mg ascorbic acid/day) vs. placebo for 8 consecutive days in 15 normal weight (BMI 20–25 kg/m²) and 15 obese (BMI > 30 kg/m²) men. The neuroenergetic content of adenosine triphosphate (ATP) and phosphocreatine (PCr) was assessed by ³¹phosphorous magnetic resonance spectroscopy, a non-invasive real-time technique to measure high-energy phosphate compounds in living tissues. Peripheral vitamin C, glucose, and insulin concentrations were measured, and spontaneous food intake was quantified by the standardized buffet test. Results: In the obese group, vitamin C application acutely suppressed the physiological insulin response on the first experimental day (p = 0.003). The following eight days of intranasal vitamin C led to higher serum vitamin C concentrations as compared to placebo (p = 0.011), compensated for the missing food intake-induced serum vitamin C rise (p ≤ 0.002), and attenuated a PCr decline (p = 0.008) in this group. Correlation analyses revealed a general link between serum vitamin C concentrations and the neuroenergetic state in both groups (p ≤ 0.033). Food intake was not influenced. Conclusions: Intranasal vitamin C application acutely improves insulin sensitivity, compensates for a vitamin C deficiency, and may act in a neuroprotective way in obese men. It could therefore be a future candidate as an adjuvant therapeutic option in obesity treatment. Full article

In vitro fertilization (IVF) exposes embryos to environmental stressors that can disrupt early development and confer long-term health risks, though the mechanisms remain poorly understood. Here, we tested the hypothesis that reducing incubation temperature during the first zygotic cleavage would promote long-term developmental stability in IVF-conceived offspring. Using a mouse model, we compared the long-term effects of standard (37 °C) versus reduced (35 °C) IVF culture temperature on energy balance, circadian rhythms, sleep architecture, and brain histone modifications. Although offspring from both IVF groups exhibited increased body mass without notable effects on glucose metabolism, significant disruptions in circadian rhythms and sleep–wake patterns were detected. The 37 °C group exhibited altered amplitudes in oxygen consumption rhythms and respiratory exchange ratios, as well as pronounced alterations in sleep–wake patterns, including reduced sleep duration and increased nighttime activity. The 35 °C group displayed intermediate phenotypes, substantiating the importance of optimizing embryo incubation parameters. These metabolic and behavioral changes were paralleled by altered histone modifications in the cerebral cortex of IVF offspring, suggesting an epigenetic basis for circadian misalignment. Our results identify disrupted circadian rhythm and sleep architecture as a novel mechanism contributing to metabolic dysfunction in IVF-conceived offspring. The partial mitigation of these effects through reduced culture temperature underscores the importance of optimizing IVF protocols to minimize long-term epigenetic and metabolic risks. Full article

Thiamine is a vitamin essential for the function of central metabolic enzymes, of which pyruvate dehydrogenase (PDH) possesses one of the broadest regulations. Diurnal effects of thiamine supplementation on energy metabolism have previously been shown for the rat brain. Here, we report data on the diurnal changes and the effects of thiamine administration to rats on the function of thiamine-dependent enzymes in the cerebral cortex, heart, and liver. The most pronounced diurnal differences were found at the level of cerebral PDH activity. Analysis of PDH phosphorylation in five rat tissues revealed diurnal and thiamine-dependent differences in the cerebral cortex and heart. The expression of tissue-specific PDH kinases PDK3 and PDK4 showed a daytime-dependent response to thiamine administration in the cerebral cortex and heart, respectively. In addition, cardiac PDK4 expression was doubled in the evening, compared to morning. Furthermore, cerebral cortex demonstrated tissue-specific diurnal changes in thiamine diphosphate (ThDP) and monophosphate levels. Elevation of blood, cardiac, and cerebral ThDP was more effective upon the evening thiamine administration. Importantly, only ThDP was elevated in the rat cerebral cortex exclusively after evening thiamine supplementation. Coenzyme role of ThDP and/or other thiamine functions in nerve tissue reduced the existing daytime changes in animal behavior and ECG parameters. The reported data on diurnal regulation of central energy metabolism as well as the diurnal difference in thiamine accumulation in the cerebral cortex, heart, and other tissues are of clinical importance, as high doses of thiamine are used for the treatment of acute thiamine deficiencies and many other mostly neurological diseases in patients. Full article

One hundred and eighteen years have passed since Alzheimer’s disease (AD) was first diagnosed by Alois Alzheimer as a multifactorial and complex neurodegenerative disorder with psychiatric components. It is inaugurated by a cascade of events initiating from amnesic-type memory impairment leading to the gradual loss of cognitive and executive capacities. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated tau protein aggregate in the brain. These pathological processes lead to neuronal loss, brain atrophy, and gliosis culminating in neurodegeneration and fueling AD. Thus, at a basic level, abnormality in the brain’s protein function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is an aging disorder caused by a combination of age-related changes and genetic and environmental factors that affect the brain over time. Its mysterious pathology seems not to be limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but to a plethora of substantial and biological processes, which have also emerged in its pathogenesis, such as a breakdown of the blood–brain barrier (BBB), patients carrying the gene variant APOE4, and the immuno-senescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) have also been observed to be early markers that may provoke pathogenic pathways that lead to or aggravate AD progression and pathology. There are numerous substantial AD features that require more understanding, such as chronic neuroinflammation, decreased glucose utilization and energy metabolism, as well as brain insulin resistance (IR). Herein, we aim to broaden our understanding and to connect the dots of the multiple comorbidities and their cumulative synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid-beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement, and the role of APOE4 allele and AD–IR pathogenic link—the shared genetics and metabolomic biomarkers between AD and IR disorders. Investment in future research brings us closer to knowing the pathogenesis of AD and paves the way to building prevention and treatment strategies. Full article

Longevity and healthy aging result from the complex interaction of genetic, epigenetic, microbial, behavioral, and environmental factors. The central nervous system—particularly the cerebral cortex—and the autonomic nervous system (ANS) play key roles in integrating external and internal signals, shaping energy metabolism, immune tone, and emotional regulation. This narrative review examines how the brain–ANS axis interacts with epigenetic regulation, telomere dynamics, the gut microbiome, and the exposome to influence biological aging and resilience. Relevant literature published between 2010 and 2025 was selected through comprehensive database searches (PubMed, Scopus, Google Scholar), with a focus on studies addressing the multisystemic determinants of aging. Emphasis is placed on lifestyle-related exposures, such as diet, physical activity, psychosocial support, and environmental quality, that modulate systemic physiology through neurovisceral pathways. Drawing on empirical findings from classical Blue Zones and recent observational research in the Cilento region of southern Italy, this review highlights how context-specific factors—such as clean air, mineral-rich water, Mediterranean dietary patterns, and strong social cohesion—may foster bioelectric, metabolic, and neuroimmune homeostasis. By integrating data from neuroscience, systems biology, and environmental epidemiology, the review proposes a comprehensive model for understanding healthy longevity and supports the development of personalized, context-sensitive strategies in geroscience and preventive medicine. Full article

Aquaporins (AQPs) are a family of transmembrane water channel proteins facilitating the transport of water and, in some cases, small solutes such as glycerol, lactate, and urea. In the central nervous system (CNS), several aquaporins play crucial roles in maintaining water homeostasis, modulating cerebrospinal fluid (CSF) circulation, regulating energy metabolism, and facilitating neuroprotection under pathological conditions. Among them, AQP2, AQP4, AQP9, and AQP11 have been implicated in traumatic and non-traumatic brain injuries. The most abundant aquaporin (AQP) in the brain, AQP4, is essential for fluid regulation, facilitating water transport across the blood–brain barrier and glymphatic clearance. AQP2 is primarily known for its function in the kidneys, but it is also expressed in brain regions related to vasopressin signaling and CSF dynamics. AQP9 acts as a channel for glycerol and lactate, thus playing a role in metabolic adaptation during brain injury. AQP11, an intracellular aquaporin, is involved in oxidative stress responses and cellular homeostasis, with emerging evidence suggesting its role in neuroprotection. Aquaporins play a dual role in brain injury; while they help maintain homeostasis, their dysregulation can exacerbate cerebral edema, metabolic dysfunction, and inflammation. In traumatic brain injury (TBI), aquaporins regulate the formation and resolution of cerebral edema. In non-traumatic brain injuries, including ischemic stroke, aneurysmal subarachnoid hemorrhage (aSAH), and intracerebral hemorrhage (ICH), aquaporins influence fluid balance, energy metabolism, and oxidative stress responses. Understanding the specific roles of AQP2, AQP4, AQP9, and AQP11 in these brain injuries may lead to new therapeutic strategies to mitigate secondary damage and improve neurological outcomes. This review explores the function of the above aquaporins in both traumatic and non-traumatic brain injuries, highlighting their potential and limitations as therapeutic targets for neuroprotection and recovery. Full article

: Alzheimer’s disease (AD) is a neurodegenerative disorder closely associated with aging, and its pathogenesis involves the interaction of multidimensional pathophysiologic processes. This review outlines the core mechanisms linking aging and AD. The amyloid cascade hypothesis emphasizes that abnormal deposition of amyloid-β (Aβ) triggers neuronal damage and synaptic dysfunction, which is exacerbated by aging-associated declines in protein clearance. Neuroinflammation, a synergistic pathogenetic factor in AD, is mediated by microglia activation, creating a vicious cycle with Aβ and tau pathology. The cholinergic hypothesis states that the degeneration of cholinergic neurons in the basal forebrain can lead to acetylcholine deficiency, which is directly associated with cognitive decline. Endothelial disorders promote neuroinflammation and metabolic waste accumulation through blood–brain barrier dysfunction and cerebral vascular abnormalities. In addition, glutamate-mediated excitotoxicity and mitochondrial dysfunction (e.g., oxidative stress and energy metabolism imbalance) further lead to neuronal death, and aging-associated declines in mitochondrial autophagy exacerbate such damage. This review also explores the application of animal models that mimic AD and aging in studying these mechanisms and summarizes therapeutic strategies targeting these pathways. Future studies need to integrate multi-targeted therapies and focus on the role of the aging microenvironment in regulating AD pathology in order to develop more effective early diagnosis and treatment options. Full article

Background: Valproic acid (VPA) is a mainstay of treatment for epilepsy. Although VPA is generally considered well tolerated, it has serious adverse effects related to the pathological impact on cerebral perfusion and oxidative metabolism, leading to progressive encephalopathy. Erythrocytes directly deliver oxygen to the tissues. To understand how the brain pathology may be related to limited oxygenation, it is important to determine whether VPA-related changes occur in the intracellular erythrocyte metabolism responsible for the oxygen transport function. Methods: To determine whether different therapeutic VPA doses affect major metabolic pathways in rat erythrocytes, the activity of rate-limiting enzymes and levels of metabolites of glycolysis, the Rapoport–Luebering shunt, the pentose phosphate pathway and the antioxidant systems were measured. Results: Our data showed that VPA-induced G6PD inhibition leads to profound oxidative stress, increased MetHb formation and decreased 2,3-DPG and ATP levels in erythrocytes that underlie the loss of their oxygen transport function, thus being a cause of a brain energy crisis that precedes encephalopathy. Conclusions: The measurement of parameters in metabolic pathways modulating the redox-signaling and oxygen-carrying capacity of erythrocytes is needed for further elucidation of complex mechanisms underlying VPA-induced brain hypoperfusion and encephalopathy. Full article

Rapid ascent to high altitudes by unacclimatized individuals significantly increases the risk of brain damage, given the brain’s heightened sensitivity to hypoxic conditions. Investigating hypoxia-tolerant animals can provide insights into adaptive mechanisms and guide prevention and treatment of hypoxic-ischemic brain injury. In this study, we exposed Brandt’s voles to simulated altitudes (100 m, 3000 m, 5000 m, and 7000 m) for 24 h and performed quantitative proteomic and phosphoproteomic analyses of brain tissue. A total of 3990 proteins and 9125 phosphorylation sites (phospho-sites) were quantified. Differentially expressed (DE) analysis revealed that while protein abundance changes were relatively modest, phosphorylation levels exhibited substantial alterations, suggesting that Brandt’s voles rapidly regulate protein structure and function through phosphorylation to maintain cellular homeostasis under acute hypoxia. Clustering analysis showed that most co-expressed proteins exhibited non-monotonic responses with increasing altitude, which were enriched in pathways related to cytokine secretion regulation and glutathione metabolism, contributing to reduced inflammation and oxidative stress. In contrast, most co-expressed phospho-sites showed monotonic changes, with phospho-proteins enriched in glycolysis and vascular smooth muscle contraction regulation. Kinase activity prediction identified nine hypoxia-responsive kinases, four of which belonging to the CAMK family. Immunoblot validated that the changes in CAMK2A activity were consistent with predictions, suggesting that CAMK may play a crucial role in hypoxic response. In conclusion, this work discovered that Brandt’s voles may cope with hypoxia through three key strategies: (1) vascular regulation to enhance cerebral blood flow, (2) glycolytic activation to increase energy production, and (3) activation of neuroprotective mechanisms. Full article

Background/Objectives: Lactate, classically considered a metabolic byproduct of anaerobic glycolysis, is implicated in ischemic acidosis and neuronal injury. The recent evidence highlights its potential role in sustaining metabolic networks and neuroprotection. This study investigates lactate’s compensatory mechanisms in ischemic brain injury by analyzing post-ischemic metabolic enrichments and inter-regional metabolite correlations. Methods: Dynamic metabolic profiling was conducted using ¹³C-labeled glucose combined with ¹H-¹³C NMR spectroscopy to quantify the metabolite enrichment changes in a murine cerebral ischemia model (n = 8). In vivo validation included intracerebroventricular pH-neutral lactate infusion in ischemic mice to assess the behavioral, electrophysiological, and mitochondrial outcomes. In vitro, HT22 hippocampal neurons underwent oxygen–glucose deprivation (OGD) with pH-controlled lactate supplementation (1 mM), followed by the evaluation of neuronal survival, mitochondrial membrane potential, and glycolytic enzyme expression. Results: NMR spectroscopy revealed a 30–50% reduction in most cerebral metabolites post-ischemia (p < 0.05), while the quantities of lactate and the related three-carbon intermediates remained stable or increased. Correlation analyses demonstrated significantly diminished inter-metabolite coordination post-ischemia, yet lactate and glutamate maintained high metabolic activity levels (r > 0.80, p < 0.01). Lactate exhibited superior cross-regional metabolic mobility compared to those of the other three-carbon intermediates. In vivo, lactate infusion improved the behavioral/electrophysiological outcomes and reduced mitochondrial damage. In the OGD-treated neurons, pH-neutral lactate (7.4) reduced mortality (p < 0.05), preserved the mitochondrial membrane potential (p < 0.05), and downregulated the glycolytic enzymes (HK, PFK, and PKM; p < 0.01), thereby attenuating H⁺ production. Conclusions: Under ischemic metabolic crisis, lactate and the three-carbon intermediates stabilize as critical substrates, compensating for global metabolite depletion. pH-neutral lactate restores energy flux, modulates the glycolytic pathways, and provides neuroprotection by mitigating acidotoxicity. Full article