bims-medebr 2023-07-02 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒07‒02
thirty-two papers selected by
Regina F. Fernández
Johns Hopkins University

The shared role of cholesterol in neuronal and peripheral inflammation.
Effect of Obesity and Osteocalcin on Brain Glucose Metabolism in Healthy Participants.
Effects of Parkin on the Mitochondrial Genome in the Heart and Brain of Mitochondrial Mutator Mice.
Transient neonatal hyperglycemia induces metabolic shifts in the rat hippocampus: a 1H NMR-based metabolomics analysis.
Syntaphilin mediates axonal growth and synaptic changes through regulation of mitochondrial transport: a potential pharmacological target for neurodegenerative diseases.
Brain metabolism in Alzheimer's disease: biological mechanisms of exercise.
Dietary Docosahexaenoic Acid and Glucose Systemic Metabolic Changes in the Mouse.
Associations between Plasma Lipid Mediators and Chronic Daily Headache Outcomes in Patients Randomized to a Low Linoleic Acid Diet with or without Added Omega-3 Fatty Acids.
Neuron-astrocyte omnidirectional signaling in neurological health and disease.
The Long-Term Neuroprotective Effect of the Endocannabinoid 2-AG and Modulation of the SGZ's Neurogenic Response after Neonatal Hypoxia-Ischemia.
Neural stem cell metabolism revisited: a critical role for mitochondria.
Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline.
Apolipoprotein E in lipid metabolism and neurodegenerative disease.
Ketosis and migraine: a systematic review of the literature and meta-analysis.
Highly Specialized Mechanisms for Mitochondrial Transport in Neurons: From Intracellular Mobility to Intercellular Transfer of Mitochondria.
The Lipogenic Enzyme Acetoacetyl-Coenzyme A Synthetase and Ketone Body Utilization for Denovo Lipid Synthesis, a Review.
History and function of the lactate receptor GPR81/HCAR1 in the brain: a putative therapeutic target for the treatment of cerebral ischemia.
Neuroprotective Efficacy of a Nanomicellar Complex of Carnosine and Lipoic Acid in a Rat Model of Rotenone-Induced Parkinson's Disease.
Human peroxisomal NAD+/NADH homeostasis is regulated by two independent NAD(H) shuttle systems.
MitoQ alleviates hippocampal damage after cerebral ischemia: The potential role of SIRT6 in regulating mitochondrial dysfunction and neuroinflammation.
The role of GLUT2 in glucose metabolism in multiple organs and tissues.
The importance of thiamine (vitamin B1) in humans.
Mitochondria dysfunction and bipolar disorder: From pathology to therapy.
Emerging roles and therapeutic potentials of sphingolipids in pathophysiology --emphasis on fatty acyl heterogeneity.
Utilization of LC-MS/MS and Drift Tube Ion Mobility for Characterizing Intact Oxidized Arachidonate-Containing Glycerophosphatidylethanolamine.
Electroconvulsive therapy triggers a reversible decrease in brain N-acetylaspartate.
Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition.
Longitudinal Imaging of Regional Brain Volumes, SV2A, and Glucose Metabolism In Huntington's Disease.
Neonatal hypoglycemia: lack of evidence for a safe management.
An integrative analysis of lipidomics and transcriptomics in various mouse brain regions in response to real-ambient PM2.5 exposure.
Set up and validation of a sensitive method to quantify prostaglandins, prostaglandin-glycerol esters and prostaglandin-ethanolamides, as well as their respective precursors.
Untargeted Metabolomic Analysis of Sjögren-Larsson Syndrome Reveals a Distinctive Pattern of Multiple Disrupted Biochemical Pathways.

Pharmacol Ther. 2023 Jun 28. pii: S0163-7258(23)00150-X. [Epub ahead of print] 108486

The shared role of cholesterol in neuronal and peripheral inflammation.

Scott B Hansen, Hao Wang.

  Neurodegeneration and its loss of cognitive function is associated with inflammation and an accumulation of lipids. In the periphery, cholesterol's uptake drives a major component of chronic inflammation. In this perspective, we describe the cellular and molecular roles of cholesterol in neuroinflammation and contrast them with those in the periphery. Incorporating shared mechanisms from the periphery, cholesterol emerges as a central signal originating in astrocytes and connecting inflammatory escalation in neurons and microglia. A cholesterol uptake pathway is proposed for neuroinflammation, and we speculate on the binding of cholesterol transport protein apolipoprotein E (apoE), including the Christchurch mutant (R136S), to cell surface receptors as a potential protective modality against uptake of astrocyte cholesterol and escalated neuroinflammation. Lastly, we discuss the molecular basis of cholesterol signaling through nanoscopic clustering and peripheral sources of cholesterol after opening of the blood brain barrier.

Keywords:  Alzheimer's; ApoE; Apolipoprotein; Cholesterol; Lipid rafts; Neuroinflammation; PIP2

DOI:  https://doi.org/10.1016/j.pharmthera.2023.108486
Brain Sci. 2023 May 31. pii: 889. [Epub ahead of print]13(6):

Effect of Obesity and Osteocalcin on Brain Glucose Metabolism in Healthy Participants.

Seunghyeon Shin, Hyun-Yeol Nam.

  We evaluated the effects of obesity and osteocalcin on glucose metabolism in the brain. A total of 179 healthy men were enrolled in this study. After preprocessing positron emission tomography images, including by performing coregistration, spatial normalization, and smoothing, regression analysis was conducted to identify the correlation between body mass index, osteocalcin, and brain glucose metabolism. Body mass index was positively correlated with brain glucose metabolism in the anterior lobe of the right cerebellum, the anterior and posterior lobes of the left cerebellum, the right middle frontal gyrus (Brodmann area 9), the right cingulate gyrus (Brodmann area 32), the right anterior cingulate (Brodmann area 32), the left middle frontal gyrus (Brodmann area 10), and the subgyral area of the left frontal lobe. Osteocalcin was negatively correlated with glucose metabolism in the anterior lobe of the left cerebellum. Body mass index was positively correlated with brain glucose metabolism in the prefrontal cortex and cerebellum. Osteocalcin levels were negatively correlated with brain glucose metabolism in the left cerebellum.

Keywords:  brain; fluorine-18-fluorodeoxyglucose; obesity; osteocalcin; positron emission tomography–computed tomography

DOI:  https://doi.org/10.3390/brainsci13060889
Adv Biol (Weinh). 2023 Jun 27. e2300154

Effects of Parkin on the Mitochondrial Genome in the Heart and Brain of Mitochondrial Mutator Mice.

Eliezer Z Lichter, Andrew J Trease, Kathryn Cooper, Kelly L Stauch, Howard S Fox.

  Mitochondrial dysfunction has been implicated in neurodegenerative diseases like Parkinson's disease (PD). This study investigates the role of Parkin, a protein involved in mitochondrial quality control, and strongly linked to PD, in the context of mitochondrial DNA (mtDNA) mutations. The authors use mitochondrial mutator mice (PolgD257A/D257A ) (Polg), which are bred with Parkin knockout (PKO) mice or mice with disinhibited Parkin (W402A). In the brain, mtDNA mutations are analyzed in synaptosomes, presynaptic neuronal terminals, which are far from neuronal soma, which likely renders mitochondria there more vulnerable compared with brain homogenate. Surprisingly, PKO results in reduced mtDNA mutations in the brain but increased control region multimer (CRMS) load in synaptosomes. In the heart, both PKO and W402A lead to increased mutations, with W402A showing more mutations in the heart than PKO. Computational analysis reveals many of these mutations are deleterious. These findings suggest that Parkin plays a tissue-dependent role in regulating mtDNA damage response, with differential effects in the brain and heart. Understanding the specific role of Parkin in different tissues may provide insights into the underlying mechanisms of PD and potential therapeutic strategies. Further investigation into these pathways can enhance the understanding of neurodegenerative diseases associated with mitochondrial dysfunction.

Keywords:  Parkinson's disease; mitochondrial dysfunction; mitochondrial genome; mtDNA; parkin

DOI:  https://doi.org/10.1002/adbi.202300154
Metab Brain Dis. 2023 Jun 26.

Transient neonatal hyperglycemia induces metabolic shifts in the rat hippocampus: a 1H NMR-based metabolomics analysis.

Yinli Huang, Junli Chen, Jiahui Lu, Hanqi Luo, Na Ying, Wei Dong, Minjie Lin, Hong Zheng.

  Diabetes has been reported to induce brain metabolic disturbance, but the effect of transient neonatal hyperglycemia (TNH) on brain metabolism remains unclear. Herein the rats were treated with a single intraperitoneal injection of 100 µg/g body weight of streptozotocin within 12 h after birth and displayed a typical clinical characteristic of TNH. Then we used NMR-based metabolomics to examine the metabolic changes in the hippocampus between TNH and normal control (Ctrl) rats at postnatal 7 days (P7) and 21 days (P21). The results show that TNH rats had significantly increased levels of N-acetyl aspartate, glutamine, aspartate and choline in the hippocampus relative to Ctrl rats at P7. Moreover, we found that the levels of alanine, myo-inositol and choline were significantly lower in TNH rats, although their blood glucose levels have been recovered to the normal level at P21. Therefore, our results suggest that TNH may have a long-term effect on hippocampal metabolic changes mainly involving neurotransmitter metabolism and choline metabolism.

Keywords:  Choline; Hippocampus; Metabolomics; Neurotransmitter; Transient hyperglycemia

DOI:  https://doi.org/10.1007/s11011-023-01255-x
J Drug Target. 2023 Jun 26. 1-14

Syntaphilin mediates axonal growth and synaptic changes through regulation of mitochondrial transport: a potential pharmacological target for neurodegenerative diseases.

Qing-Yun Wu, Hui-Lin Liu, Hai-Yan Wang, Kai-Bin Hu, Ping Liao, Sen Li, Zai-Yun Long, Xiu-Min Lu, Yong-Tang Wang.

  Mitochondria are a crucial energy source for maintaining neuronal growth and synaptic function. Neurons possess unique morphological characteristics, which make the proper regulation of mitochondrial transport essential for meeting their energy demands. Syntaphilin (SNPH) is capable of specifically targeting the outer membrane of axonal mitochondria, anchoring them to microtubules, and thereby preventing their transport. SNPH also interacts with other mitochondrial proteins to regulate mitochondrial transport. The regulation of mitochondrial transport and anchoring mediated by SNPH is indispensable for axonal growth during neuronal development, maintenance of ATP levels during neuronal synaptic activity, and regeneration of mature neurons following damage. Precise blocking of SNPH may be an effective therapeutic strategy for neurodegenerative diseases and related mental disorders.

Keywords:  Syntaphilin; mitochondrial transport; neurodegenerative diseases; neuronal regeneration; synaptic plasticity

DOI:  https://doi.org/10.1080/1061186X.2023.2230522
Transl Neurodegener. 2023 06 26. 12(1): 33

Brain metabolism in Alzheimer's disease: biological mechanisms of exercise.

Longfei Xu, Ran Liu, Yingkai Qin, Tianhui Wang.

  Alzheimer's disease (AD) is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors, accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain. At the cellular and molecular levels, the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities, compromised bioenergetics, impaired lipid metabolism, and reduced overall metabolic capacity, which lead to abnormal neural network activity and impaired neuroplasticity, thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles. The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise. Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state, inhibit different pathophysiological molecular pathways associated with AD, influence the pathological process of AD, and exert a protective effect, there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise. Here, we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD, including glucose metabolism, lipid metabolism, Aβ metabolism and transport, iron metabolism and tau pathology. How metabolic states influence brain health is also presented. A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.

Keywords:  Alzheimer’s disease; Aβ metabolism; Exercise; Glucose and lipid metabolism; Iron metabolism; Tau pathology

DOI:  https://doi.org/10.1186/s40035-023-00364-y
Nutrients. 2023 Jun 08. pii: 2679. [Epub ahead of print]15(12):

Dietary Docosahexaenoic Acid and Glucose Systemic Metabolic Changes in the Mouse.

Bruce A Watkins, John W Newman, George A Kuchel, Oliver Fiehn, Jeffrey Kim.

  The endocannabinoid system (ECS) participates in regulating whole body energy balance. Overactivation of the ECS has been associated with the negative consequence of obesity and type 2 diabetes. Since activators of the ECS rely on lipid-derived ligands, an investigation was conducted to determine whether dietary PUFA could influence the ECS to affect glucose clearance by measuring metabolites of macronutrient metabolism. C57/blk6 mice were fed a control or DHA-enriched semi-purified diet for a period of 112 d. Plasma, skeletal muscle, and liver were collected after 56 d and 112 d of feeding the diets for metabolomics analysis. Key findings characterized a shift in glucose metabolism and greater catabolism of fatty acids in mice fed the DHA diet. Glucose use and promotion of fatty acids as substrate were found based on levels of metabolic pathway intermediates and altered metabolic changes related to pathway flux with DHA feeding. Greater levels of DHA-derived glycerol lipids were found subsequently leading to the decrease of arachidonate-derived endocannabinoids (eCB). Levels of 1- and 2-arachidonylglcerol eCB in muscle and liver were lower in the DHA diet group compared to controls. These findings demonstrate that DHA feeding in mice alters macronutrient metabolism and may restore ECS tone by lowering arachidonic acid derived eCB.

Keywords:  C57/blk6 mice; DHA; endocannabinoids; liver; metabolomics; muscle; plasma

DOI:  https://doi.org/10.3390/nu15122679
Metabolites. 2023 May 25. pii: 690. [Epub ahead of print]13(6):

Associations between Plasma Lipid Mediators and Chronic Daily Headache Outcomes in Patients Randomized to a Low Linoleic Acid Diet with or without Added Omega-3 Fatty Acids.

Qing Shen, Jun Yang, Daisy Zamora, Mark Horowitz, Keturah R Faurot, Beth A MacIntosh, J Douglas Mann, Bruce D Hammock, Christopher E Ramsden, Ameer Y Taha.

  A previous report showed that 12-week lowering of dietary omega-6 linoleic acid (LA) coupled with increased omega-3 polyunsaturated fatty acid (PUFA) intake (H3-L6 diet) reduced headache frequency and improved quality of life in patients with chronic daily headaches (CDHs) compared to dietary LA reduction alone (L6 diet). The trial also showed that targeted dietary manipulation alters PUFA-derived lipid mediators and endocannabinoids. However, several additional classes of lipid mediators associated with pain in preclinical models were not measured. The current secondary analysis investigated whether the clinical benefits of the H3-L6 diet were related to changes in plasma unesterified PUFA-derived lipid mediators known to be involved in nociception, including prostanoids. Lipid mediators were measured by ultra-high-pressure liquid chromatography coupled with tandem mass-spectrometry. Compared to baseline, dietary LA lowering with or without added omega-3 fatty acids did not alter unesterified n-6 PUFA-derived lipid mediators, although several species derived from LA, di-homo-gamma-linolenic acid, and arachidonic acid were positively associated with headache frequency and intensity, as well as mental health burden. Alpha-linolenic acid (ALA)-derived metabolites were also associated with increased headache frequency and intensity, although they did not change from the baseline in either dietary group. Compared to baseline, docosahexaenoic acid (DHA)-derived epoxides were more elevated in the H3-L6 group compared to the L6 group. Diet-induced elevations in plasma DHA-epoxides were associated with reduced headache frequency, better physical and mental health, and improved quality of life (p < 0.05). Prostanoids were not detected, except for PGF2-alpha, which was not associated with any outcomes. This study demonstrates that diet-induced changes in DHA-epoxides were associated with pain reduction in patients with chronic headaches, whereas n-6 PUFA and ALA metabolites were associated with nociception. Lipid mediator associations with mental health and quality of life paralleled pain management outcomes in this population. The findings point to a network of multiple diet-modifiable lipid mediator targets for pain management in individuals with CDHs.

Keywords:  diet; fish; lipids; pain; psychological distress; quality of life

DOI:  https://doi.org/10.3390/metabo13060690
Front Mol Neurosci. 2023 ;16 1169320

Neuron-astrocyte omnidirectional signaling in neurological health and disease.

Dhruba Pathak, Krishnan Sriram.

  Astrocytes are an abundantly distributed population of glial cells in the central nervous system (CNS) that perform myriad functions in the normal and injured/diseased brain. Astrocytes exhibit heterogeneous phenotypes in response to various insults, a process known as astrocyte reactivity. The accuracy and precision of brain signaling are primarily based on interactions involving neurons, astrocytes, oligodendrocytes, microglia, pericytes, and dendritic cells within the CNS. Astrocytes have emerged as a critical entity within the brain because of their unique role in recycling neurotransmitters, actively modulating the ionic environment, regulating cholesterol and sphingolipid metabolism, and influencing cellular crosstalk in diverse neural injury conditions and neurodegenerative disorders. However, little is known about how an astrocyte functions in synapse formation, axon specification, neuroplasticity, neural homeostasis, neural network activity following dynamic surveillance, and CNS structure in neurological diseases. Interestingly, the tripartite synapse hypothesis came to light to fill some knowledge gaps that constitute an interaction of a subpopulation of astrocytes, neurons, and synapses. This review highlights astrocytes' role in health and neurological/neurodegenerative diseases arising from the omnidirectional signaling between astrocytes and neurons at the tripartite synapse. The review also recapitulates the disruption of the tripartite synapse with a focus on perturbations of the homeostatic astrocytic function as a key driver to modulate the molecular and physiological processes toward neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; astrocyte-neuron communication; glutamic acid; neurodegenerative diseases; synaptic signaling; tripartite synapse

DOI:  https://doi.org/10.3389/fnmol.2023.1169320
Pharmaceutics. 2023 Jun 07. pii: 1667. [Epub ahead of print]15(6):

The Long-Term Neuroprotective Effect of the Endocannabinoid 2-AG and Modulation of the SGZ's Neurogenic Response after Neonatal Hypoxia-Ischemia.

Gorane Beldarrain, Enrique Hilario, Idoia Lara-Celador, Marc Chillida, Ana Catalan, Antonia Ángeles Álvarez-Diaz, Daniel Alonso-Alconada.

  Neonatal hypoxia-ischemia (HI) often causes hypoxic-ischemic encephalopathy (HIE), a neurological condition that can lead to overall disability in newborns. The only treatment available for affected neonates is therapeutic hypothermia; however, cooling is not always effective to prevent the deleterious effects of HI, so compounds such as cannabinoids are currently under research as new therapies. Modulating the endocannabinoid system (ECS) may reduce brain damage and/or stimulate cell proliferation at the neurogenic niches. Further, the long-term effects of cannabinoid treatment are not so clear. Here, we studied the middle- and long-term effects of 2-AG, the most abundant endocannabinoid in the perinatal period after HI in neonatal rats. At middle-term (postnatal day 14), 2-AG reduced brain injury and increased SGZ's cell proliferation and the number of neuroblasts. At post-natal day 90, the treatment with the endocannabinoid showed global and local protection, suggesting long-lasting neuroprotective effects of 2-AG after neonatal HI in rats.

Keywords:  2-AG; endocannabinoid system; neonatal hypoxia-ischemia; neurogenesis; neuroprotection

DOI:  https://doi.org/10.3390/pharmaceutics15061667
Trends Endocrinol Metab. 2023 Jun 26. pii: S1043-2760(23)00110-8. [Epub ahead of print]

Neural stem cell metabolism revisited: a critical role for mitochondria.

Valentina Scandella, Francesco Petrelli, Darcie L Moore, Simon M G Braun, Marlen Knobloch.

  Metabolism has emerged as a key regulator of stem cell behavior. Mitochondria are crucial metabolic organelles that are important for differentiated cells, yet considered less so for stem cells. However, recent studies have shown that mitochondria influence stem cell maintenance and fate decisions, inviting a revised look at this topic. In this review, we cover the current literature addressing the role of mitochondrial metabolism in mouse and human neural stem cells (NSCs) in the embryonic and adult brain. We summarize how mitochondria are implicated in fate regulation and how substrate oxidation affects NSC quiescence. We further explore single-cell RNA sequencing (scRNA-seq) data for metabolic signatures of adult NSCs, highlight emerging technologies reporting on metabolic signatures, and discuss mitochondrial metabolism in other stem cells.

Keywords:  metabolism; mitochondria; neural stem cells; quiescence

DOI:  https://doi.org/10.1016/j.tem.2023.05.008
J Neurochem. 2023 Jun 30.

Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline.

Thea Anderson, Sumeet Sharma, Michael A Kelberman, Christopher Ware, Nanxi Guo, Zhaohui Qin, David Weinshenker, Marise B Parent.

  Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar "Western" diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.

Keywords:  Alzheimer’s; TgF344-AD; hippocampus; noradrenergic; obesity; transcriptome

DOI:  https://doi.org/10.1111/jnc.15900
Trends Endocrinol Metab. 2023 Jun 23. pii: S1043-2760(23)00092-9. [Epub ahead of print]

Apolipoprotein E in lipid metabolism and neurodegenerative disease.

Linda G Yang, Zachary M March, Roxan A Stephenson, Priyanka S Narayan.

  Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E (APOE), modulate risk and resilience in several neurodegenerative diseases including late-onset Alzheimer's disease (LOAD). Allelic variants of the gene, APOE, alter the lipid metabolism of cells and tissues and have been broadly associated with several other cellular and systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to alter disease-related phenotypes and consequently, attenuate disease risk and impart resilience to multiple neurodegenerative diseases. We review the molecular, cellular, and tissue-level alterations to lipid metabolism that arise from different APOE isoforms. These changes in lipid metabolism could help to elucidate disease mechanisms and tune neurodegenerative disease risk and resilience.

Keywords:  Alzheimer's disease; apolipoprotein E; lipid metabolism; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.tem.2023.05.002
Front Nutr. 2023 ;10 1204700

Ketosis and migraine: a systematic review of the literature and meta-analysis.

Lenycia de Cassya Lopes Neri, Cinzia Ferraris, Guido Catalano, Monica Guglielmetti, Ludovica Pasca, Elena Pezzotti, Adriana Carpani, Anna Tagliabue.

  Introduction: Headaches are a prevalent disorder worldwide, and there is compelling evidence that certain dietary interventions could provide relief from attacks. One promising approach is ketogenic therapy, which replaces the brain's glucose fuel source with ketone bodies, potentially reducing the frequency or severity of headaches.Aim: This study aims to conduct a systematic review of the scientific literature on the impact of ketosis on migraine, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method.
Results: After a careful selection process and bias evaluation, 10 articles were included in the review, primarily from Italy. The bias assessment indicated that 50% of the selected articles had a low risk of bias in all domains, with the randomization process being the most problematic domain. Unfortunately, the evaluation of ketosis was inconsistent between articles, with some assessing ketonuria, some assessing ketonemia, and some not assessing ketosis levels at all. Therefore, no association could be made between the level of ketosis and the prevention or reduction of migraine attacks. The ketogenic therapies tested in migraine treatments included the very low-calorie ketogenic diet (VLCKD, n = 4), modified Atkins diet (MAD, n = 3), classic ketogenic diet (cKDT, n = 2), and the administration of an exogenous source of beta-hydroxybutyrate (BHB). The meta-analysis, despite reporting high heterogeneity, found that all interventions had an overall significant effect (Z = 9.07, p < 0.00001; subgroup differences, Chi2 = 9.19, dif = 3, p = 0.03; I2, 67.4%), regardless of the type of endogenous or exogenous induction of ketosis.
Conclusion: The initial findings of this study suggest that metabolic ketogenic therapy may provide some benefit in treating migraines and encourage further studies, especially randomized clinical trials with appropriate and standardized methodologies. The review strongly recommends the use of the adequate measurement of ketone levels during ketogenic therapy to monitor adherence to the treatment and improve knowledge of the relationship between ketone bodies and efficacy.
Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022330626.

Keywords:  ketogenic diet; ketosis; meta-analysis; migraine disorders; systematic review

DOI:  https://doi.org/10.3389/fnut.2023.1204700
Biomolecules. 2023 06 03. pii: 938. [Epub ahead of print]13(6):

Highly Specialized Mechanisms for Mitochondrial Transport in Neurons: From Intracellular Mobility to Intercellular Transfer of Mitochondria.

Marta Zaninello, Camilla Bean.

  The highly specialized structure and function of neurons depend on a sophisticated organization of the cytoskeleton, which supports a similarly sophisticated system to traffic organelles and cargo vesicles. Mitochondria sustain crucial functions by providing energy and buffering calcium where it is needed. Accordingly, the distribution of mitochondria is not even in neurons and is regulated by a dynamic balance between active transport and stable docking events. This system is finely tuned to respond to changes in environmental conditions and neuronal activity. In this review, we summarize the mechanisms by which mitochondria are selectively transported in different compartments, taking into account the structure of the cytoskeleton, the molecular motors and the metabolism of neurons. Remarkably, the motor proteins driving the mitochondrial transport in axons have been shown to also mediate their transfer between cells. This so-named intercellular transport of mitochondria is opening new exciting perspectives in the treatment of multiple diseases.

Keywords:  TNTs; cytoskeleton; microtubules; mitochondria; mitochondrial transplantation; neuron; transport

DOI:  https://doi.org/10.3390/biom13060938
J Lipid Res. 2023 Jun 23. pii: S0022-2275(23)00080-9. [Epub ahead of print] 100407

The Lipogenic Enzyme Acetoacetyl-Coenzyme A Synthetase and Ketone Body Utilization for Denovo Lipid Synthesis, a Review.

James D Bergstrom.

  Acetoacetyl-CoA synthetase (AACS) is the key enzyme in the anabolic utilization of ketone bodies (KBs) for denovo lipid synthesis, a process that bypasses citrate and ATP citrate lyase. This review shows that AACS is a highly regulated, cytosolic and lipogenic enzyme and that many tissues can readily use KBs for denovo lipid synthesis. AACS has a low, micromolar Km for acetoacetate (AcAc) and supply of AcAc should not limit its activity in the fed state. In many tissues AACS appears to be regulated in conjunction with the need for cholesterol, but in adipose tissue it seems tied to fatty acid synthesis. KBs are readily utilized as substrates for lipid synthesis in lipogenic tissues including liver, adipose tissue, lactating mammary gland, skin, intestinal mucosa, adrenals and developing brain. In numerous studied cases, KBs served several-fold better than glucose as substrates for lipid synthesis and when present, KBs suppressed the utilization of glucose for lipid synthesis. Here it is hypothesized that a physiological role for the utilization of KBs for lipid synthesis is a metabolic process of lipid interconversion. Fatty acids are converted to KBs in liver and then the KBs are utilized to synthesize cholesterol and other long-chainfatty acids in liver and non-hepatic tissues. The conversion of fatty acids to cholesterol via the KBs may be a particularly important example of lipid interconversion. Utilizing KBs for lipid synthesis is glucose sparing and probably is important with low carbohydrate diets. Metabolic situations and tissues where lipid interconversion may be important are discussed.

Keywords:  ATP citrate lyase; Acetoacetate; Denovo lipid synthesis; anabolic role for ketone bodies; cholesterol synthesis; glucose sparing; lipid interconversion

DOI:  https://doi.org/10.1016/j.jlr.2023.100407
Neuroscience. 2023 Jun 28. pii: S0306-4522(23)00292-0. [Epub ahead of print]

History and function of the lactate receptor GPR81/HCAR1 in the brain: a putative therapeutic target for the treatment of cerebral ischemia.

Anna Clara Machado Colucci, Isadora D'Ávila Tassinari, Eloísa da Silveira Loss, Luciano Stürmer de Fraga.

  GPR81 is a G-protein coupled receptor (GPCR) discovered in 2001, but deorphanized only 7 years later, when its affinity for lactate as an endogenous ligand was demonstrated. More recently, GPR81 expression and distribution in the brain were also confirmed and the function of lactate as a volume transmitter has been suggested since then. These findings shed light on a new function of lactate acting as a signaling molecule in the central nervous system, in addition to its well-known role as a metabolic fuel for neurons. GPR81 seems to act as a metabolic sensor, coupling energy metabolism, synaptic activity, and blood flow. Activation of this receptor leads to Gi-mediated downregulation of adenylyl cyclase and subsequent reduction in cAMP levels, regulating several downstream pathways. Recent studies have also suggested the potential role of lactate as a neuroprotective agent, mainly under brain ischemic conditions. This effect is usually attributed to the metabolic role of lactate, but the underlying mechanisms need further investigation and could be related to lactate signaling via GPR81. The activation of GPR81 showed promising results for neuroprotection; it modulates many processes involved in the pathophysiology of ischemia. In this review, we summarize the history of GPR81, starting with its deorphanization; then, we discuss GPR81 expression and distribution, signaling transduction cascades, and neuroprotective roles. Lastly, we propose GPR81 as a potential target for the treatment of cerebral ischemia.

Keywords:  GPR81; HCAR1; L-lactate; cerebral ischemia; neuroprotection

DOI:  https://doi.org/10.1016/j.neuroscience.2023.06.022
Antioxidants (Basel). 2023 Jun 04. pii: 1215. [Epub ahead of print]12(6):

Neuroprotective Efficacy of a Nanomicellar Complex of Carnosine and Lipoic Acid in a Rat Model of Rotenone-Induced Parkinson's Disease.

Olga Kulikova, Dmitry Troshev, Daniil Berezhnoy, Sergey Stvolinsky, Yulia Timoshina, Denis Abaimov, Olga Muzychuk, Alexander Latanov, Tatiana Fedorova.

  Oxidative stress, accompanied by mitochondrial dysfunction, is a key mechanism involved in the pathogenesis of Parkinson's disease (PD). Both carnosine and lipoic acid are potent antioxidants, the applicability of which in therapy is hindered by their limited bioavailability. This study aimed to evaluate the neuroprotective properties of a nanomicellar complex of carnosine and lipoic acid (CLA) in a rotenone-induced rat model of PD. Parkinsonism was induced via the administration of 2 mg/kg rotenone over the course of 18 days. Two doses of intraperitoneal CLA (25 mg/kg and 50 mg/kg) were administered alongside rotenone to assess its neuroprotective effect. At 25 mg/kg CLA decreased muscle rigidity and partially restored locomotor activity in animals that received rotenone. Furthermore, it caused an overall increase in brain tissue antioxidant activity, accompanied by a 19% increase in neuron density in the substantia nigra and increased dopamine levels in the striatum relative to animals that only received rotenone. Based on the acquired results, it may be concluded that CLA have neuroprotective properties and could potentially be beneficial in PD treatment when used in conjunction with the base therapy.

Keywords:  Parkinson’s disease; antioxidants; carnosine; lipoic acid; neuroprotection; rat; rotenone

DOI:  https://doi.org/10.3390/antiox12061215
Free Radic Biol Med. 2023 Jun 22. pii: S0891-5849(23)00507-5. [Epub ahead of print]

Human peroxisomal NAD+/NADH homeostasis is regulated by two independent NAD(H) shuttle systems.

Serhii Chornyi, Cláudio F Costa, Lodewijk IJlst, Marc Fransen, Ronald J A Wanders, Carlo W T van Roermund, Hans R Waterham.

  Reduced (NADH) and oxidized (NAD+) nicotinamide adenine dinucleotides are ubiquitous hydride-donating/accepting cofactors that are essential for cellular bioenergetics. Peroxisomes are single-membrane-bounded organelles that are involved in multiple lipid metabolism pathways, including beta-oxidation of fatty acids, and which contain several NAD(H)-dependent enzymes. Although maintenance of NAD(H) homeostasis in peroxisomes is considered essential for peroxisomal beta-oxidation, little is known about the regulation thereof. To resolve this issue, we have developed methods to specifically measure intraperoxisomal NADH levels in human cells using peroxisome-targeted NADH biosensors. By targeted CRISPR-Cas9-mediated genome editing of human cells, we showed with these sensors that the NAD+/NADH ratio in cytosol and peroxisomes are closely connected and that this crosstalk is mediated by intraperoxisomal lactate and malate dehydrogenases, generated via translational stop codon readthrough of the LDHB and MDH1 mRNAs. Our study provides evidence for the existence of two independent redox shuttle systems in human peroxisomes that regulate peroxisomal NAD+/NADH homeostasis. This is the first study that shows a specific metabolic function of protein isoforms generated by translational stop codon readthrough in humans.

Keywords:  Beta-oxidation; Bioenergetics; Cofactor; Dehydrogenase; Metabolism; Redox balance

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.06.020
Life Sci. 2023 Jun 27. pii: S0024-3205(23)00530-1. [Epub ahead of print]328 121895

MitoQ alleviates hippocampal damage after cerebral ischemia: The potential role of SIRT6 in regulating mitochondrial dysfunction and neuroinflammation.

Ayman A Ibrahim, Sherif S Abdel Mageed, Marwa M Safar, Mohammed F El-Yamany, Mamdouh A Oraby.

  AIMS: Mitochondrial perturbations are the major culprit of the inflammatory response during the initial phase of cerebral ischemia. The present study explored the neuroprotective effect of the mitochondrial-targeted antioxidant, Mitoquinol (MitoQ), against hippocampal neuronal loss in an experimental model of brain ischemia/reperfusion (I/R) injury.MAIN METHODS: Rats were subjected to common carotid artery occlusion for 45 min, followed by reperfusion for 24 h. MitoQ (2 mg/kg; i.p daily) was administered for 7 successive days prior to the induction of brain ischemia.
KEY FINDINGS: I/R rats exhibited hippocampal damage evidenced by aggravated mitochondrial oxidative stress, thereby enhancing mtROS and oxidized mtDNA, together with inhibiting mtGSH. Mitochondrial biogenesis and function were also affected, as reflected by the reduction of PGC-1α, TFAM, and NRF-1 levels, as well as loss of mitochondrial membrane potential (△Ψm (. These changes were associated with neuroinflammation, apoptosis, impairment of cognitive function as well as hippocampal neurodegenerative changes in histopathological examination. Notably, SIRT6 was suppressed. Pretreatment with MitoQ markedly potentiated SIRT6, modulated mitochondrial oxidative status and restored mitochondrial biogenesis and function. In addition, MitoQ alleviated the inflammatory mediators, TNF-α, IL-18, and IL-1β and dampened GFAB immunoexpression along with downregulation of cleaved caspase-3 expression. Reversal of hippocampal function by MitoQ was accompanied by improved cognitive function and hippocampal morphological aberrations.
SIGNIFICANCE: This study suggests that MitoQ preserved rats' hippocampi from I/R insults via maintenance of mitochondrial redox status, biogenesis, and activity along with mitigation of neuroinflammation and apoptosis, thereby regulating SIRT6.

Keywords:  Apoptosis; Ischemia/reperfusion; MitoQ; Neuroinflammation; SIRT6 and stroke

DOI:  https://doi.org/10.1016/j.lfs.2023.121895
Mol Biol Rep. 2023 Jun 26.

The role of GLUT2 in glucose metabolism in multiple organs and tissues.

Bo Sun, Hui Chen, Jisu Xue, Peiwu Li, Xu Fu.

  The glucose transporter family has an important role in the initial stage of glucose metabolism; Glucose transporters 2 (GLUTs, encoded by the solute carrier family 2, SLC2A genes) is the major glucose transporter in β-cells of pancreatic islets and hepatocytes but is also expressed in the small intestine, kidneys, and central nervous system; GLUT2 has a relatively low affinity to glucose. Under physiological conditions, GLUT2 transports glucose into cells and allows the glucose concentration to reach balance on the bilateral sides of the cellular membrane; Variation of GLUT2 is associated with various endocrine and metabolic disorders; In this study, we discussed the role of GLUT2 in participating in glucose metabolism and regulation in multiple organs and tissues and its effects on maintaining glucose homeostasis.

Keywords:  Blood glucose homeostasis; Blood glucose regulation; GLUT2; Glucose metabolism

DOI:  https://doi.org/10.1007/s11033-023-08535-w
Biosci Rep. 2023 Jun 30. pii: BSR20230374. [Epub ahead of print]

The importance of thiamine (vitamin B1) in humans.

Małgorzata Mrowicka, Jerzy Mrowicki, Grzegorz Dragan, Ireneusz Majsterek.

  Thiamine (thiamin, B1) is a vitamin necessary for proper cell function. It exists in a free form as a thiamine, or as a mono-, di- or triphosphate. Thiamine plays a special role in the body as a coenzyme necessary for the metabolism of carbohydrates, fats and proteins. In addition, it participates in the cellular respiration and oxidation of fatty acids: in malnourished people, high doses of glucose result in acute thiamine deficiency. It also participates in energy production in the mitochondria and protein synthesis. In addition, it is also needed to ensure the proper functioning of the central and peripheral nervous system, where it is involved in neurotransmitter synthesis. Its deficiency leads to mitochondrial dysfunction, lactate and pyruvate accumulation, and consequently to focal thalamic degeneration, manifested as Wernicke's encephalopathy or Wernicke-Korsakoff syndrome. It can also lead to severe or even fatal neurologic and cardiovascular complications, including heart failure, neuropathy leading to ataxia and paralysis, confusion, or delirium. The most common risk factor for thiamine deficiency is alcohol abuse. This paper presents current knowledge of the biological functions of thiamine, its antioxidant properties, and the effects of its deficiency in the body.

Keywords:  antioxidant properties; biological functions; deficiency in thiamine: causes and effects; neuropathy; thiamine; thiamine esters

DOI:  https://doi.org/10.1042/BSR20230374
IBRO Neurosci Rep. 2023 Jun;14 407-418

Mitochondria dysfunction and bipolar disorder: From pathology to therapy.

Xin-Jieh Lam, Bingzhe Xu, Pei-Ling Yeo, Pike-See Cheah, King-Hwa Ling.

  Bipolar disorder (BD) is one of the major psychiatric diseases in which the impairment of mitochondrial functions has been closely connected or associated with the disease pathologies. Different lines of evidence of the close connection between mitochondria dysfunction and BD were discussed with a particular focus on (1) dysregulation of energy metabolism, (2) effect of genetic variants, (3) oxidative stress, cell death and apoptosis, (4) dysregulated calcium homeostasis and electrophysiology, and (5) current as well as potential treatments targeting at restoring mitochondrial functions. Currently, pharmacological interventions generally provide limited efficacy in preventing relapses or recovery from mania or depression episodes. Thus, understanding mitochondrial pathology in BD will lead to novel agents targeting mitochondrial dysfunction and formulating new effective therapy for BD.

Keywords:  Anaerobic respiration; Apoptosis; Energy; Gene variant; Metabolism; Oxidative phosphorylation; Oxidative stress

DOI:  https://doi.org/10.1016/j.ibneur.2023.04.002
J Genet Genomics. 2023 Jun 24. pii: S1673-8527(23)00142-X. [Epub ahead of print]

Emerging roles and therapeutic potentials of sphingolipids in pathophysiology --emphasis on fatty acyl heterogeneity.

Jinming Mu, Sin Man Lam, Guanghou Shui.

  Sphingolipids not only exert structural roles in cellular membranes, but also act as signaling molecules in various physiological and pathological processes. A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human diseases. Moreover, blood sphingolipids can also be used as biomarkers for disease diagnosis. This review summarizes the biosynthesis, metabolism, and pathological roles of sphingolipids, with emphasis on the biosynthesis of ceramide, the precursor for the biosynthesis of complex sphingolipids with different fatty acyl chains. The possibility of using sphingolipids for disease prediction, diagnosis, and treatment is also discussed. Targeting endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.

Keywords:  Biomarker; Ceramide; Microdomain; Sphingolipids; Therapeutic targets

DOI:  https://doi.org/10.1016/j.jgg.2023.06.006
J Am Soc Mass Spectrom. 2023 Jun 27.

Utilization of LC-MS/MS and Drift Tube Ion Mobility for Characterizing Intact Oxidized Arachidonate-Containing Glycerophosphatidylethanolamine.

Yulemni Morel, Jace W Jones.

  Lipid peroxidation is a key component in the pathogenesis of numerous disease states, where the oxidative damage of lipids frequently leads to membrane dysfunction and subsequent cellular death. Glycerophosphoethanolamine (PE) is the second most abundant phospholipid found in cellular membranes and, when oxidized, has been identified as an executor of ferroptotic cell death. PE commonly exists in the plasmalogen form, where the presence of the vinyl ether bond and its enrichment in polyunsaturated fatty acids make it especially susceptible to oxidative degradation. This results in a multitude of oxidized products complicating identification and often requiring several analytical techniques for interpretation. In the present study, we outline an analytical approach for the structural characterization of intact oxidized products of arachidonate-containing diacyl and plasmalogen PE. Intact oxidized PE structures, including structural and positional isomers, were identified using complementary liquid chromatography techniques, drift tube ion mobility, and high-resolution tandem mass spectrometry. This work establishes a comprehensive method for the analysis of intact lipid peroxidation products and provides an important pathway to investigate how lipid peroxidation initially impacts glycerophospholipids and their role in redox biology.

Keywords:  lipid peroxidation; mass spectrometry; oxidized lipid structures; plasmalogen

DOI:  https://doi.org/10.1021/jasms.3c00083
Front Psychiatry. 2023 ;14 1155689

Electroconvulsive therapy triggers a reversible decrease in brain N-acetylaspartate.

Vera J Erchinger, Alexander R Craven, Lars Ersland, Ketil J Oedegaard, Christoffer A Bartz-Johannessen, Åsa Hammar, Jan Haavik, Frank Riemer, Ute Kessler, Leif Oltedal.

  Introduction: Based on previous research on electroconvulsive therapy (ECT) we have proposed a model where disruption, potentiation, and rewiring of brain networks occur in sequence and serve as the underlying therapeutic mechanism of ECT. This model implies that a temporary disturbance of neuronal networks (disruption) is followed by a trophic effect (potentiation), which enables the rewiring of neuronal circuits to a more euthymic functioning brain. We hypothesized that disruption of neuronal networks could trigger biochemical alterations leading to a temporary decrease in N-acetylaspartate (tNAA, considered a marker of neuronal integrity), while choline (a membrane component), myo-Inositol (mI, astroglia marker), and glutamate/glutamine (Glx, excitatory neurotransmitter) were postulated to increase. Previous magnetic resonance spectroscopy studies, reporting diverse findings, have used two different referencing methods - creatine ratios and tissue corrected values referenced to water - for the quantification of brain metabolites. Changes in creatine during ECT have also been reported, which may confound estimates adopting this as an internal reference.Methods: Using MR spectroscopy, we investigated 31 moderately to severely depressed patients and 19 healthy controls before, during, and after ECT or at similar time points (for controls). We tested whether biochemical alterations in tNAA, choline, mI, and Glx lend support to the disrupt, potentiate, and rewire hypothesis. We used both creatine ratios and water-scaled values for the quantification of brain metabolites to validate the results across referencing methods.
Results: Levels of tNAA in the anterior cingulate cortex decreased after an ECT treatment series (average 10.6 sessions) by 6% (p = 0.007, creatine ratio) and 3% (p = 0.02, water referenced) but returned to baseline 6 months after ECT. Compared to after treatment series tNAA levels at 6-month follow-up had increased in both creatine ratio (+6%, p < 0.001) and water referenced data (+7%, p < 0.001). Findings for other brain metabolites varied and could not be validated across referencing methods.
Discussion: Our findings suggest that prior research must be interpreted with care, as several referencing and processing methods have been used in the past. Yet, the results for tNAA were robust across quantification methods and concur with relevant parts of the disrupt, potentiate, and rewire model.

Keywords:  1H-MRS nuclear magnetic resonance spectroscopy; choline; depression; electroconvulsive therapy; glutamate; myoinositol; neurometabolites

DOI:  https://doi.org/10.3389/fpsyt.2023.1155689
Acta Physiol (Oxf). 2023 Jun 27. e14016

Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition.

Sotiria Tavoulari, Maximilian Sichrovsky, Edmund R S Kunji.

  The mitochondrial pyruvate carrier (MPC) resides in the mitochondrial inner membrane, where it links cytosolic and mitochondrial metabolism by transporting pyruvate produced in glycolysis into the mitochondrial matrix. Due to its central metabolic role, it has been proposed as a potential drug target for diabetes, non-alcoholic fatty liver disease, neurodegeneration, and cancers relying on mitochondrial metabolism. Little is known about the structure and mechanism of MPC, as the proteins involved were only identified a decade ago and technical difficulties concerning their purification and stability have hindered progress in functional and structural analyses. The functional unit of MPC is a hetero-dimer comprising two small homologous membrane proteins, MPC1/MPC2 in humans, with the alternative complex MPC1L/MPC2 forming in the testis, but MPC proteins are found throughout the tree of life. The predicted topology of each protomer consists of an amphipathic helix followed by three transmembrane helices. An increasing number of inhibitors are being identified, expanding MPC pharmacology and providing insights into the inhibitory mechanism. Here, we provide critical insights on the composition, structure, and function of the complex and we summarize the different classes of small molecule inhibitors and their potential in therapeutics.

Keywords:  metabolism; mitochondria; pyruvate transport; small molecule inhibitors; transport mechanism

DOI:  https://doi.org/10.1111/apha.14016
Mov Disord. 2023 Jun 29.

Longitudinal Imaging of Regional Brain Volumes, SV2A, and Glucose Metabolism In Huntington's Disease.

Aline Delva, Koen Van Laere, Wim Vandenberghe.

  BACKGROUND: Development of disease-modifying treatments for Huntington's disease (HD) could be aided by the use of imaging biomarkers of disease progression. Positron emission tomography (PET) with 11 C-UCB-J, a radioligand for the brain-wide presynaptic marker synaptic vesicle protein 2A (SV2A), detects more widespread brain changes in early HD than volumetric magnetic resonance imaging (MRI) and 18 F-fludeoxyglucose (18 F-FDG) PET, but longitudinal 11 C-UCB-J PET data have not been reported. The aim of this study was to compare the sensitivity of 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI for detection of longitudinal changes in early HD.METHODS: Seventeen HD mutation carriers (six premanifest and 11 early manifest) and 13 healthy controls underwent 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI at baseline (BL) and after 21.4 ± 2.7 months (Y2). Within-group and between-group longitudinal clinical and imaging changes were assessed.
RESULTS: The HD group showed significant 2-year worsening of Unified Huntington's Disease Rating Scale motor scores. There was significant longitudinal volume loss within the HD group in caudate (-4.5% ± 3.8%), putamen (-3.6% ± 3.5%), pallidum (-3.0% ± 2.7%), and frontal cortex (-2.0% ± 2.1%) (all P < 0.001). Within the HD group there was longitudinal loss of putaminal SV2A binding (6.4% ± 8.8%, P = 0.01) and putaminal glucose metabolism (-2.8% ± 4.4%, P = 0.008), but these changes were not significant after correction for multiple comparisons. Premanifest subjects at BL only had significantly lower SV2A binding than controls in basal ganglia structures, but at Y2 additionally had significant SV2A loss in frontal and parietal cortex, indicating spread of SV2A loss from subcortical to cortical regions.
CONCLUSIONS: Volumetric MRI may be more sensitive than 11 C-UCB-J PET and 18 F-FDG PET for detection of 2-year brain changes in early HD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  11C-UCB-J PET; 18F-FDG PET; Huntington's disease; structural MRI; synaptic density

DOI:  https://doi.org/10.1002/mds.29501
Front Endocrinol (Lausanne). 2023 ;14 1179102

Neonatal hypoglycemia: lack of evidence for a safe management.

Marcia Roeper, Henrike Hoermann, Sebastian Kummer, Thomas Meissner.

  Neonatal hypoglycemia affects up to 15% of all newborns. Despite the high prevalence there is no uniform definition of neonatal hypoglycemia, and existing guidelines differ significantly in terms of when and whom to screen for hypoglycemia, and where to set interventional thresholds and treatment goals. In this review, we discuss the difficulties to define hypoglycemia in neonates. Existing knowledge on different strategies to approach this problem will be reviewed with a focus on long-term neurodevelopmental outcome studies and results of interventional trials. Furthermore, we compare existing guidelines on the screening and management of neonatal hypoglycemia. We summarize that evidence-based knowledge about whom to screen, how to screen, and how to manage neonatal hypoglycemia is limited - particularly regarding operational thresholds (single values at which to intervene) and treatment goals (what blood glucose to aim for) to reliably prevent neurodevelopmental sequelae. These research gaps need to be addressed in future studies, systematically comparing different management strategies to progressively optimize the balance between prevention of neurodevelopmental sequelae and the burden of diagnostic or therapeutic procedures. Unfortunately, such studies are exceptionally challenging because they require large numbers of participants to be followed for years, as mild but relevant neurological consequences may not become apparent until mid-childhood or even later. Until there is clear, reproducible evidence on what blood glucose levels may be tolerated without negative impact, the operational threshold needs to include some safety margin to prevent potential long-term neurocognitive impairment from outweighing the short-term burden of hypoglycemia prevention during neonatal period.

Keywords:  at-risk neonates; brain damage; neonatal hypoglycemia; treatment guidelines; treatment threshold

DOI:  https://doi.org/10.3389/fendo.2023.1179102
Sci Total Environ. 2023 Jun 24. pii: S0048-9697(23)03735-X. [Epub ahead of print] 165112

An integrative analysis of lipidomics and transcriptomics in various mouse brain regions in response to real-ambient PM2.5 exposure.

Shuangjian Qin, Huixian Zeng, Qizhen Wu, Qingqing Li, Mohammed Zeeshan, Lizhu Ye, Yue Jiang, Rui Zhang, Xinhang Jiang, Miao Li, Rong Zhang, Wen Chen, Wei-Chun Chou, Guang-Hui Dong, Dao-Chuan Li, Xiao-Wen Zeng.

  Exposure to Fine particulate matter (PM2.5) has been associated with various neurological disorders. However, the underlying mechanisms of PM2.5-induced adverse effects on the brain are still not fully defined. Multi-omics analyses could offer novel insights into the mechanisms of PM2.5-induced brain dysfunction. In this study, a real-ambient PM2.5 exposure system was applied to male C57BL/6 mice for 16 weeks, and lipidomics and transcriptomics analysis were performed in four brain regions. The findings revealed that PM2.5 exposure led to 548, 283, 304, and 174 differentially expressed genes (DEGs), as well as 184, 89, 228, and 49 distinctive lipids in the hippocampus, striatum, cerebellum, and olfactory bulb, respectively. Additionally, in most brain regions, PM2.5-induced DEGs were mainly involved in neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, and calcium signaling pathway, while PM2.5-altered lipidomic profile were primarily enriched in retrograde endocannabinoid signaling and biosynthesis of unsaturated fatty acids. Importantly, mRNA-lipid correlation networks revealed that PM2.5-altered lipids and DEGs were obviously enriched in pathways involving in bile acid biosynthesis, De novo fatty acid biosynthesis, and saturated fatty acids beta-oxidation in brain regions. Furthermore, multi-omics analyses revealed that the hippocampus was the most sensitive part to PM2.5 exposure. Specifically, dysregulation of Pla2g1b, Pla2g, Alox12, Alox15, and Gpx4 induced by PM2.5 were closely correlated to the disruption of alpha-linolenic acid, arachidonic acid and linoleic acid metabolism in the hippocampus. In summary, our findings highlight differential lipidomic and transcriptional signatures of various brain regions by real-ambient PM2.5 exposure, which will advance our understanding of potential mechanisms of PM2.5-induecd neurotoxicity.

Keywords:  Bile acid biosynthesis; Brain regions; Fine particulate matter; Multi-omics; Neurotoxicity

DOI:  https://doi.org/10.1016/j.scitotenv.2023.165112
Prostaglandins Other Lipid Mediat. 2023 Jun 28. pii: S1098-8823(23)00060-6. [Epub ahead of print] 106763

Set up and validation of a sensitive method to quantify prostaglandins, prostaglandin-glycerol esters and prostaglandin-ethanolamides, as well as their respective precursors.

Adrien Paquot, Juan Bestard-Escalas, Giulio G Muccioli.

  Arachidonic acid-derived prostaglandins are widely studied for their role in inflammation. However, besides arachidonic acid, other arachidonic moiety-containing lipids can be metabolized by COX-2. Indeed, the endocannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide, AEA) can follow the same biochemical pathways than arachidonic acid leading to the formation of prostaglandin-glycerol esters (PG-G) and prostaglandin-ethanolamides (or prostamides, PG-EA), respectively. The data reported so far support the interest of these bioactive lipids in inflammatory conditions. However, there is only a handful of methods described for their quantification in biological matrices. Moreover, given the shared biochemical pathways for arachidonic acid, 2-AG and AEA, a method allowing for the quantification of these precursors and the corresponding prostaglandin derivatives appears as largely needed. Thus, we report here the development and validation of a single run UPLC-MS/MS quantification method allowing the quantification of these endocannabinoids-derived mediators together with the classical prostaglandin. Moreover, we applied the method to the quantification of these lipids in vitro (using lipopolysaccharides-activated J774 macrophage cells) and in vivo in several tissues from DSS-induced colitis mice. This femtomole-range method should improve the understanding of the interaction between these lipid mediators and inflammation.

Keywords:  LC-MS; PGD(2)-G; PGE(2)-G; eicosanoid; fatty acid

DOI:  https://doi.org/10.1016/j.prostaglandins.2023.106763
Metabolites. 2023 May 23. pii: 682. [Epub ahead of print]13(6):

Untargeted Metabolomic Analysis of Sjögren-Larsson Syndrome Reveals a Distinctive Pattern of Multiple Disrupted Biochemical Pathways.

Hongying Daisy Dai, Fang Qiu, Kimberly Jackson, Marcus Fruttiger, William B Rizzo.

  Sjögren-Larsson syndrome (SLS) is a rare inherited neurocutaneous disease characterized by ichthyosis, spastic diplegia or tetraplegia, intellectual disability and a distinctive retinopathy. SLS is caused by bi-allelic mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal lipid metabolism. The biochemical abnormalities in SLS are not completely known, and the pathogenic mechanisms leading to symptoms are still unclear. To search for pathways that are perturbed in SLS, we performed untargeted metabolomic screening in 20 SLS subjects along with age- and sex-matched controls. Of 823 identified metabolites in plasma, 121 (14.7%) quantitatively differed in the overall SLS cohort from controls; 77 metabolites were decreased and 44 increased. Pathway analysis pointed to disrupted metabolism of sphingolipids, sterols, bile acids, glycogen, purines and certain amino acids such as tryptophan, aspartate and phenylalanine. Random forest analysis identified a unique metabolomic profile that had a predictive accuracy of 100% for discriminating SLS from controls. These results provide new insight into the abnormal biochemical pathways that likely contribute to disease in SLS and may constitute a biomarker panel for diagnosis and future therapeutic studies.

Keywords:  fatty alcohol; fatty aldehyde; ichthyosis; intellectual disability; lipid metabolism; pathogenesis; spasticity

DOI:  https://doi.org/10.3390/metabo13060682