bims-medebr 2022-03-20 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022‒03‒20
nineteen papers selected by
Regina F. Fernández
Johns Hopkins University

Migraine, Brain Glucose Metabolism and the "Neuroenergetic" Hypothesis: A Scoping Review.
Impact of Donepezil on Brain Glucose Metabolism Assessed Using [18F]2-Fluoro-2-deoxy-D-Glucose Positron Emission Tomography Imaging in a Mouse Model of Alzheimer's Disease Induced by Intracerebroventricular Injection of Amyloid-Beta Peptide.
Cerebral Energy Status and Altered Metabolism in Early Brain Injury After Aneurysmal Subarachnoid Hemorrhage: A Prospective 31P-MRS Pilot Study.
Aging related impairment of brain microvascular bioenergetics involves oxidative phosphorylation and glycolytic pathways.
Lipoproteins in the Central Nervous System: From Biology to Pathobiology.
The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis.
Temporal changes in the brain lipidome during neurodevelopment of Smith-Lemli-Opitz syndrome mice.
Mapping oxidative metabolism in the human brain with calibrated fMRI in health and disease.
Hormone-sensitive lipase is localized at synapses and is necessary for normal memory functioning in mice.
Regional cerebral hypometabolism on 18F-FDG PET/CT scan in delirium is independent of acute illness and dementia.
Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients.
Rapid and gentle immunopurification of brain synaptic vesicles.
Lactate infusion as therapeutical intervention: a scoping review.
Structural and molecular characterization of paraventricular thalamic glucokinase-expressing neuronal circuits in the mouse.
Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration.
Targeting lipophagy in macrophages improves repair in multiple sclerosis.
N-Acetylcysteine Mitigates Social Dysfunction in a Rat Model of Autism Normalizing Glutathione Imbalance and the Altered Expression of Genes Related to Synaptic Function in Specific Brain Areas.
Astrocyte regulation of cerebral blood flow during hypoglycemia.
The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease.

J Pain. 2022 Mar 13. pii: S1526-5900(22)00039-6. [Epub ahead of print]

Migraine, Brain Glucose Metabolism and the "Neuroenergetic" Hypothesis: A Scoping Review.

Lorenzo Del Moro, Eugenia Rota, Elenamaria Pirovano, Innocenzo Rainero.

  Increasing evidence suggests that migraine may be the result of an impaired brain glucose metabolism. Several studies have reported brain mitochondrial dysfunction, impaired brain glucose metabolism and gray matter volume reduction in specific brain areas of migraineurs. Furthermore, peripheral insulin resistance, a condition demonstrated in several studies, may extend to the brain, leading to brain insulin resistance. This condition has been proven to downregulate insulin receptors, both in astrocytes and neurons, triggering a reduction in glucose uptake and glycogen synthesis, mainly during high metabolic demand. This scoping review examines the clinical, epidemiologic and pathophysiologic data supporting the hypothesis that abnormalities in brain glucose metabolism may generate a mismatch between the brain's energy reserve and metabolic expenditure, triggering migraine attacks. Moreover, alteration in glucose homeostasis could generate a chronic brain energy deficit promoting migraine chronification. Lastly, insulin resistance may link migraine with its comorbidities, like obesity, depression, cognitive impairment and cerebrovascular diseases. Perspective: Although additional experimental studies are needed to support this novel "neuroenergetic" hypothesis, brain insulin resistance in migraineurs may unravel the pathophysiological mechanisms of the disease, explaining the migraine chronification and connecting migraine with comorbidities. Therefore, this hypothesis could elucidate novel potential approaches for migraine treatment.

Keywords:  Migraine; brain insulin resistance; glucose; insulin resistance; insulin sensitivity; postprandial hypoglycaemia

DOI:  https://doi.org/10.1016/j.jpain.2022.02.006
Front Neurosci. 2022 ;16 835577

Impact of Donepezil on Brain Glucose Metabolism Assessed Using [18F]2-Fluoro-2-deoxy-D-Glucose Positron Emission Tomography Imaging in a Mouse Model of Alzheimer's Disease Induced by Intracerebroventricular Injection of Amyloid-Beta Peptide.

Gaëlle Hugon, Sébastien Goutal, Marie Sarazin, Michel Bottlaender, Fabien Caillé, Marine Droguerre, Mathieu Charvériat, Alexandra Winkeler, Nicolas Tournier.

  Translational methods are needed to monitor the impact of the Alzheimer's disease (AD) and therapies on brain function in animal models and patients. The formation of amyloid plaques was investigated using [18F]florbetapir autoradiography in a mouse model of AD consisting in unilateral intracerebroventricular (i.c.v) injection of amyloid peptide Aβ25-35. Then, an optimized positron emission tomography (PET) imaging protocol using [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) was performed to estimate brain glucose metabolism: [18F]FDG was injected in awake animals to allow for 40 min brain uptake in freely moving mice. Anesthesia was then induced for 30 min PET acquisition to capture the slow and poorly reversible brain uptake of [18F]FDG. Impact of donepezil (0.25 mg/kg daily, 7 days, orally) on brain function was investigated in AD mice (n = 6 mice/group). Formation of amyloid plaques could not be detected using autoradiography. Compared with sham controls (injection of scramble peptide), significant decrease in [18F]FDG uptake was observed in the AD group in the subcortical volume of the ipsilateral hemisphere. Donepezil restored normal glucose metabolism by selectively increasing glucose metabolism in the affected subcortical volume but not in other brain regions. In mice, [18F]FDG PET imaging can be optimized to monitor impaired brain function associated with i.c.v injection of Aβ25-35, even in the absence of detectable amyloid plaque. This model recapitulates the regional decrease in [18F]FDG uptake observed in AD patients. [18F]FDG PET imaging can be straightforwardly transferred to AD patients and may aid the development of certain therapies designed to restore the altered brain function in AD.

Keywords:  Alzheimer’s disease; Alzheimer’s mouse model; PET imaging; awake brain imaging; donepezil; functional imaging (positron emission tomography)

DOI:  https://doi.org/10.3389/fnins.2022.835577
Front Neurol. 2022 ;13 831537

Cerebral Energy Status and Altered Metabolism in Early Brain Injury After Aneurysmal Subarachnoid Hemorrhage: A Prospective 31P-MRS Pilot Study.

Stephanie Alice Treichl, Wing Mann Ho, Ruth Steiger, Astrid Ellen Grams, Andreas Rietzler, Markus Luger, Elke Ruth Gizewski, Claudius Thomé, Ondra Petr.

  Background: Acute changes of cerebral energy metabolism in early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) may play a crucial role for overall neurological outcome. However, direct detection of these alterations is limited. Phosphorous magnetic resonance spectroscopy (31P-MRS) is a molecular-based advanced neuroimaging technique allowing measurements of pathophysiological processes and tissue metabolism based on various phosphorous compound metabolites. This method may provide objective assessment of both primary and secondary changes.Objective: The aim of this pilot study was to evaluate the feasibility and the diagnostic potential of early 31P-MRS in aSAH.
Methods: Patients with aSAH treated for ruptured aneurysms between July 2016 and October 2017 were prospectively included in the study. 3-Tesla-MRI including 31P-MRS was performed within the first 72 h after hemorrhage. Data of the vascular territories of the anterior, middle, and posterior cerebral arteries (ACA, MCA, PCA) and the basal ganglia were separately analyzed and compared with data of a healthy age- and sex-matched control group. Phosphorous compound metabolites were quantified, and ratios of these metabolites were further evaluated. Influence of treatment modality, clinical conditions, and analgosedation were analyzed.
Results: Data of 13 patients were analyzed. 31P-MRS showed significant changes in cerebral energy metabolism after aSAH in all cerebrovascular territories. Both PCr/ATP and PCr/Pi ratio were notably increased (P < 0.001). Also, Pi/ATP was significantly decreased in all cerebrovascular territories (P = 0.014). PME/PDE ratio was overall significant decreased (P < 0.001).
Conclusion: 31P-MRS is a promising non-invasive imaging tool for the assessment of changes in energy metabolism after aSAH. It allows a detailed insight into EBI and seems to harbor a high potential for clinical practice.

Keywords:  31-P-MR-spectroscopy; brain metabolism; early brain injury; energy status; subarachnoid hemorrhage

DOI:  https://doi.org/10.3389/fneur.2022.831537
J Cereb Blood Flow Metab. 2022 Mar 16. 271678X211069266

Aging related impairment of brain microvascular bioenergetics involves oxidative phosphorylation and glycolytic pathways.

Siva Svp Sakamuri, Venkata N Sure, Lahari Kolli, Wesley R Evans, Jared A Sperling, Gregory J Bix, Xiaoying Wang, Dmitriy N Atochin, Walter L Murfee, Ricardo Mostany, Prasad Vg Katakam.

  Mitochondrial and glycolytic energy pathways regulate the vascular functions. Aging impairs the cerebrovascular function and increases the risk of stroke and cognitive dysfunction. The goal of our study is to characterize the impact of aging on brain microvascular energetics. We measured the oxygen consumption and extracellular acidification rates of freshly isolated brain microvessels (BMVs) from young (2-4 months) and aged (20-22 months) C57Bl/6 male mice. Cellular ATP production in BMVs was predominantly dependent on oxidative phosphorylation (OXPHOS) with glucose as the preferred energy substrate. Aged BMVs exhibit lower ATP production rate with diminished OXPHOS and glycolytic rate accompanied by increased utilization of glutamine. Impairments of glycolysis displayed by aged BMVs included reduced compensatory glycolysis whereas impairments of mitochondrial respiration involved reduction of spare respiratory capacity and proton leak. Aged BMVs showed reduced levels of key glycolysis proteins including glucose transporter 1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 but normal lactate dehydrogenase activity. Mitochondrial protein levels were mostly unchanged whereas citrate synthase activity was reduced, and glutamate dehydrogenase was increased in aged BMVs. Thus, for the first time, we identified the dominant role of mitochondria in bioenergetics of BMVs and the alterations of the energy pathways that make the aged BMVs vulnerable to injury.

Keywords:  ATP; Oxygen consumption rate; extracellular acidification rate; glycolysis; oxidative phosphorylation

DOI:  https://doi.org/10.1177/0271678X211069266
Annu Rev Biochem. 2022 Feb 18.

Lipoproteins in the Central Nervous System: From Biology to Pathobiology.

Ana-Caroline Raulin, Yuka A Martens, Guojun Bu.

The brain, as one of the most lipid-rich organs, heavily relies on lipid transport and distribution to maintain homeostasis and neuronal function. Lipid transport mediated by lipoprotein particles, which are complex structures composed of apolipoproteins and lipids, has been thoroughly characterized in the periphery. Although lipoproteins in the central nervous system (CNS) were reported over half a century ago, the identification of APOE4 as the strongest genetic risk factor for Alzheimer's disease has accelerated investigation of the biology and pathobiology of lipoproteins in the CNS. This review provides an overview of the different components of lipoprotein particles, in particular apolipoproteins, and their involvements in both physiological functions and pathological mechanisms in the CNS. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-biochem-032620-104801
Acta Neuropathol Commun. 2022 Mar 16. 10(1): 35

The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis.

Xiaojing Bai, Meiting Mai, Kai Yao, Mengqi Zhang, Yue Huang, Wenbin Zhang, Xiaorou Guo, Yixuan Xu, Ying Zhang, Atikam Qurban, Lijie Duan, Jimei Bu, Jianfeng Zhang, Junfeng Wu, Yongfei Zhao, Xiangshan Yuan, Hengbing Zu.

  Previous studies show that 3β-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In brain cholesterol synthetic metabolism, DHCR24 is known as the heavily key synthetase in cholesterol synthesis. Moreover, mutations of DHCR24 gene result in inhibition of the enzymatic activity of DHCR24, causing brain cholesterol deficiency and desmosterol accumulation. Furthermore, in vitro studies also demonstrated that DHCR24 knockdown lead to the inhibition of cholesterol synthesis, and the decrease of plasma membrane cholesterol and intracellular cholesterol level. Obviously, DHCR24 could play a crucial role in maintaining cholesterol homeostasis via the control of cholesterol synthesis. Over the past two decades, accumulating data suggests that DHCR24 activity is downregulated by major risk factors for AD, suggesting a potential link between DHCR24 downregulation and AD pathogenesis. Thus, the brain cholesterol loss seems to be induced by the major risk factors for AD, suggesting a possible causative link between brain cholesterol loss and AD. According to previous data and our study, we further found that the reduced cholesterol level in plasma membrane and intracellular compartments by the deficiency of DHCR24 activity obviously was involved in β-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal that the brain cholesterol loss and lipid raft disorganization are obviously linked to neuropathological impairments which are associated with AD pathogenesis. Therefore, based on previous data and research on DHCR24, we suppose that the brain cholesterol deficiency/loss might be involved in the pathogenesis of AD.

Keywords:  Alzheimer’s disease; Cholesterol; Cholesterol deficiency; DHCR24; Hypothesis; Pathogenesis

DOI:  https://doi.org/10.1186/s40478-022-01338-3
Analyst. 2022 Mar 16.

Temporal changes in the brain lipidome during neurodevelopment of Smith-Lemli-Opitz syndrome mice.

Amy Li, Kelly M Hines, Dylan H Ross, James W MacDonald, Libin Xu.

Neurodevelopment is an intricately orchestrated program of cellular events that occurs with tight temporal and spatial regulation. While it is known that the development and proper functioning of the brain, which is the second most lipid rich organ behind adipose tissue, greatly rely on lipid metabolism and signaling, the temporal lipidomic changes that occur throughout the course of neurodevelopment have not been investigated. Smith-Lemli-Opitz syndrome is a metabolic disorder caused by genetic mutations in the DHCR7 gene, leading to defective 3β-hydroxysterol-Δ7-reductase (DHCR7), the enzyme that catalyzes the last step of the Kandutsch-Russell pathway of cholesterol synthesis. Due to the close regulatory relationship between sterol and lipid homeostasis, we hypothesize that altered or dysregulated lipid metabolism beyond the primary defect of cholesterol biosynthesis is present in the pathophysiology of SLOS. Herein, we applied our HILIC-IM-MS method and LiPydomics Python package to streamline an untargeted lipidomics analysis of developing mouse brains in both wild-type and Dhcr7-KO mice, identifying lipids at Level 3 (lipid species level: lipid class/subclass and fatty acid sum composition). We compared relative lipid abundances throughout development, from embryonic day 12.5 to postnatal day 0 and determined differentially expressed brain lipids between wild-type and Dhcr7-KO mice at specific developmental time points, revealing lipid metabolic pathways that are affected in SLOS beyond the cholesterol biosynthesis pathway, such as glycerolipid, glycerophospholipid, and sphingolipid metabolism. Implications of the altered lipid metabolic pathways in SLOS pathophysiology are discussed.

DOI: https://doi.org/10.1039/d2an00137c
J Cereb Blood Flow Metab. 2022 Mar 16. 271678X221077338

Mapping oxidative metabolism in the human brain with calibrated fMRI in health and disease.

J Jean Chen, Biranavan Uthayakumar, Fahmeed Hyder.

  Conventional functional MRI (fMRI) with blood-oxygenation level dependent (BOLD) contrast is an important tool for mapping human brain activity non-invasively. Recent interest in quantitative fMRI has renewed the importance of oxidative neuroenergetics as reflected by cerebral metabolic rate of oxygen consumption (CMRO2) to support brain function. Dynamic CMRO2 mapping by calibrated fMRI require multi-modal measurements of BOLD signal along with cerebral blood flow (CBF) and/or volume (CBV). In human subjects this "calibration" is typically performed using a gas mixture containing small amounts of carbon dioxide and/or oxygen-enriched medical air, which are thought to produce changes in CBF (and CBV) and BOLD signal with minimal or no CMRO2 changes. However non-human studies have demonstrated that the "calibration" can also be achieved without gases, revealing good agreement between CMRO2 changes and underlying neuronal activity (e.g., multi-unit activity and local field potential). Given the simpler set-up of gas-free calibrated fMRI, there is evidence of recent clinical applications for this less intrusive direction. This up-to-date review emphasizes technological advances for such translational gas-free calibrated fMRI experiments, also covering historical progression of the calibrated fMRI field that is impacting neurological and neurodegenerative investigations of the human brain.

Keywords:  Calibrated fMRI; calibrated BOLD; dual calibration; gas calibration; gas-free calibration; glucose metabolism; gradient-spin echo; hypercapnic calibration; hyperoxic calibration; local-field potential; multi-unit activity; neuroenergetics; neuronal BOLD; oxidative metabolism; vascular BOLD

DOI:  https://doi.org/10.1177/0271678X221077338
J Lipid Res. 2022 Mar 14. pii: S0022-2275(22)00028-1. [Epub ahead of print] 100195

Hormone-sensitive lipase is localized at synapses and is necessary for normal memory functioning in mice.

Cecilia Skoug, Cecilia Holm, João M N Duarte.

  Hormone-sensitive lipase (HSL) is mainly present in adipose tissue where it hydrolyses diacylglycerol. Although expression of HSL has also been reported in the brain, its presence in different cellular compartments is uncertain, and its role in regulating brain lipid metabolism remains hitherto unexplored. We hypothesized HSL might play a role in regulating the availability of bioactive lipids necessary for neuronal function, and therefore investigated whether dampening HSL activity could lead to brain dysfunction. In mice, we found HSL protein and enzymatic activity throughout the brain, both localized within neurons and enriched in synapses. HSL-null mice were then analyzed using a battery of behavioral tests. Relative to wild-type littermates, HSL-null mice showed impaired short- and long-term memory, yet preserved exploratory behaviurs. Molecular analysis of the cortex and hippocampus showed increased expression of genes involved in glucose utilization in the hippocampus, but not cortex, of HSL-null mice compared to controls. Furthermore, lipidomics analyses indicated an impact of HSL deletion on the profile of bioactive lipids, including a decrease in endocannabinoids and eicosanoids that are known to modulate neuronal activity, cerebral blood flow, and inflammation processes. Accordingly, mild increases in the expression of pro-inflammatory cytokines in HSL mice compared to littermates were suggestive of low-grade inflammation. We conclude that HSL has a homeostatic role in maintaining pools of lipids required for normal brain function. It remains to be tested, however, whether the recruitment of HSL for the synthesis of these lipids occurs during increased neuronal activity, or whether HSL participates in neuroinflammatory responses.

Keywords:  animal models; cerebral blood flow; cortex; eicosanoids; endocannabinoids; exploratory behavior; hippocampus; inflammation; lipidomics; metabolism

DOI:  https://doi.org/10.1016/j.jlr.2022.100195
Alzheimers Dement. 2022 Mar 15.

Regional cerebral hypometabolism on 18F-FDG PET/CT scan in delirium is independent of acute illness and dementia.

Anita Nitchingham, Jarett Vanz-Brian Pereira, Eva A Wegner, Vincent Oxenham, Jacqueline Close, Gideon A Caplan.

  INTRODUCTION: Delirium is associated with new onset dementia and accelerated cognitive decline; however, its pathophysiology remains unknown. Cerebral glucose metabolism previously seen in delirium may have been attributable to acute illness and/or dementia. We aimed to statistically map cerebral glucose metabolism attributable to delirium.METHODS: We assessed cerebral glucose metabolism using 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) in sick, older patients with and without delirium, all without clinical dementia (N = 20). Strict exclusion criteria were adopted to minimize the effect of established confounders on FDG-PET.
RESULTS: Patients with delirium demonstrated hypometabolism in the bilateral thalami and right superior frontal, right posterior cingulate, right infero-lateral anterior temporal, and left superior parietal cortices. Regional hypometabolism correlated with delirium severity and performance on neuropsychological testing.
DISCUSSION: In patients with acute illness but without clinical dementia, delirium is accompanied by regional cerebral hypometabolism. While some hypometabolic regions may represent preclinical Alzheimer's disease (AD), thalamic hypometabolism is atypical of AD and consistent with the clinical features that are unique to delirium.

Keywords:  18F-fluorodeoxyglucose positron emission tomography; cerebral glucose metabolism; delirium; dementia; neuroimaging

DOI:  https://doi.org/10.1002/alz.12604
Sci Adv. 2022 Mar 18. 8(11): eabj4716

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients.

Raghavendra Singh, Adam Bartok, Melanie Paillard, Ashley Tyburski, Melanie Elliott, György Hajnóczky.

Dysregulation of mitochondrial Ca2+ homeostasis has been linked to neurodegenerative diseases. Mitochondrial Ca2+ uptake is mediated via the calcium uniporter complex that is primarily regulated by MICU1, a Ca2+-sensing gatekeeper. Recently, human patients with MICU1 loss-of-function mutations were diagnosed with neuromuscular and cognitive impairments. While studies in patient-derived cells revealed altered mitochondrial calcium signaling, the neuronal pathogenesis was difficult to study. To fill this void, we created a neuron-specific MICU1-KO mouse model. These animals show progressive, abnormal motor and cognitive phenotypes likely caused by the degeneration of motor neurons in the spinal cord and the cortex. We found increased susceptibility to mitochondrial Ca2+ overload-induced excitotoxic insults and cell death in MICU1-KO neurons and MICU1-deficient patient-derived cells, which can be blunted by inhibiting the mitochondrial permeability transition pore. Thus, our study identifies altered neuronal mitochondrial Ca2+ homeostasis as causative in the clinical symptoms of MICU1-deficient patients and highlights potential therapeutic targets.

DOI: https://doi.org/10.1126/sciadv.abj4716
J Neurosci. 2022 Mar 16. pii: JN-RM-2521-21. [Epub ahead of print]

Rapid and gentle immunopurification of brain synaptic vesicles.

Mazdak M Bradberry, Shweta Mishra, Zhao Zhang, Lanxi Wu, Justin M McKetney, Martha M Vestling, Joshua J Coon, Edwin R Chapman.

Current methods to isolate synaptic vesicles (SVs), the organellar quanta of synaptic transmission, require highly specialized materials and up to 24 hours. These technical obstacles have thus far limited the study of SVs in models of synaptic function and pathophysiology. Here, we describe techniques for the rapid isolation of SVs by immunoprecipitation with widely available antibodies conjugated to magnetic beads. We report that the inexpensive rho1D4 monoclonal antibody binds SVs and show that elution with the 1D4 peptide yields native vesicles that are ≥ 10-fold purer than those obtained with classical techniques. These methods substantially widen the accessibility of SVs, enabling their purification in 60-90 minutes for downstream analyses including mass spectrometry and cryo-electron microscopy. Immunopurified SV preparations from mouse brain contained apolipoprotein E (ApoE), the low-density lipoprotein (LDL) receptor Lrp1, and enzymes involved in lipid metabolism, suggesting that SVs may play direct roles in lipid homeostasis and lipoprotein trafficking at the nerve terminal.SIGNIFICANCE STATEMENTSynaptic vesicles (SVs) are small organelles that form and recycle at nerve terminals to enable synaptic transmission. Much remains unknown about the processes that enable the formation and function of SVs. Moreover, nerve terminals appear to be particularly vulnerable to pathophysiologic processes underlying neurodegenerative diseases and schizophrenia. While techniques to purify synaptic vesicles thus have the potential to yield significant insights into physiology and pathophysiology of nerve terminals, current methods rely on either esoteric materials or expression of transgenes. This paper addresses these problems by establishing robust, efficient methods for SV purification using widely available materials, and it highlights several promising areas of future study arising from proteomic analyses of immunopurified SVs.

DOI: https://doi.org/10.1523/JNEUROSCI.2521-21.2022
Eur J Pediatr. 2022 Mar 18.

Lactate infusion as therapeutical intervention: a scoping review.

Loes A van Gemert, Bastiaan E de Galan, Ron A Wevers, Rob Ter Heine, Michèl A Willemsen.

  Traditionally, clinicians consider lactate as a waste product of anaerobic glycolysis. Interestingly, research has shown that lactate may serve as an alternative fuel for the brain to protect it against harm. The increasing scientific awareness of the potential beneficial side of lactate, however, is entering the clinic rather slowly. Following this, and realizing that the application of potential novel therapeutic strategies in pediatric populations often lags behind the development in adults, this review summarizes the key data on therapeutic use of intravenous infusion of sodium lactate in humans. PubMed and clinicaltrial.gov were searched up until November 2021 focusing on interventional studies in humans. Thirty-four articles were included in this review, with protocols of lactate infusion in adults with diabetes mellitus, traumatic brain injury, Alzheimer's disease, and cardiac disease. One study on lactate infusion in children was also included. Results of our literature search show that sodium lactate can be safely administrated, without major side effects. Additionally, the present literature clearly shows the potential benefits of therapeutic lactate infusion under certain pathological circumstances, including rather common clinical conditions like traumatic brain injury.CONCLUSION: This review shows that lactate is a save, alternative energy source for the adult brain warranting studies on the potential therapeutic effects of sodium lactate infusion in children.
WHAT IS KNOWN: • Lactate is generally considered a waste product of anaerobic glycolysis. However, lactate also is an alternative fuel for different organs, including the brain. • Lactate infusion is not incorporated in standard care for any patient population.
WHAT IS NEW: • Thirty-four studies investigated the therapeutic use of intravenous sodium lactate in different patient populations, all with different study protocols. • Literature shows that lactate infusion may have beneficial effects in case of hypoglycemia, traumatic brain injury, and cardiac failure without the risk of major side effects.

Keywords:  Brain energy metabolism; Review; Sodium lactate; Therapeutic lactate infusion

DOI:  https://doi.org/10.1007/s00431-022-04446-3
J Comp Neurol. 2022 Mar 18.

Structural and molecular characterization of paraventricular thalamic glucokinase-expressing neuronal circuits in the mouse.

Sevasti Gaspari, Simon Quenneville, Ana Rodriguez Sanchez-Archidona, Bernard Thorens, Sophie Croizier.

  The thalamic paraventricular nucleus (PVT) is a structure highly interconnected with several nuclei ranging from forebrain to hypothalamus and brainstem. Numerous rodent studies have examined afferent and efferent connections of the PVT and their contribution to behavior, revealing its important role in the integration of arousal cues. However, the majority of these studies used a region-oriented approach, without considering the neuronal subtype diversity of the nucleus. In the present study, we provide the anatomical and transcriptomic characterization of a subpopulation of PVT neurons molecularly defined by the expression of glucokinase (Gck). Combining a genetically modified mouse model with viral tracing approaches, we mapped both the anterograde and the retrograde projections of Gck-positive neurons of the anterior PVT (GckaPVT ). Our results demonstrated that GckaPVT neurons innervate several nuclei throughout the brain axis. The strongest connections are with forebrain areas associated with reward and stress and with hypothalamic structures involved in energy balance and feeding regulation. Furthermore, transcriptomic analysis of the Gck-expressing neurons revealed that they are enriched in receptors for hypothalamic-derived neuropeptides, adhesion molecules, and obesity and diabetes susceptibility transcription factors. Using retrograde labeling combined with immunohistochemistry and in situ hybridization, we identify that GckaPVT neurons receive direct inputs from well-defined hypothalamic populations, including arginine-vasopressin-, melanin-concentrating hormone-, orexin-, and proopiomelanocortin-expressing neurons. This detailed anatomical and transcriptomic characterization of GckaPVT neurons provides a basis for functional studies of the integration of homeostatic and hedonic aspects of energy homeostasis, and for deciphering the potential role of these neurons in obesity and diabetes development.

Keywords:  TRAP; anterograde and retrograde tract tracing; glucokinase-expressing neurons; hypothalamic nuclei; neurohormones; neuropeptides; neurotransmitters; paraventricular nucleus of the thalamus

DOI:  https://doi.org/10.1002/cne.25312
Degener Neurol Neuromuscul Dis. 2022 ;12 31-59

Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration.

Sidharth Mehan, Sonalika Bhalla, Ehraz Mehmood Siddiqui, Nidhi Sharma, Ambika Shandilya, Andleeb Khan.

  Dementia is a chronic, irreversible condition marked by memory loss, cognitive decline, and mental instability. It is clinically related to various progressive neurological diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's. The primary cause of neurological disorders is insulin desensitization, demyelination, oxidative stress, and neuroinflammation accompanied by various aberrant proteins such as amyloid-β deposits, Lewy bodies accumulation, tau formation leading to neurofibrillary tangles. Impaired insulin signaling is directly associated with amyloid-β and α-synuclein deposition, as well as specific signaling cascades involved in neurodegenerative diseases. Insulin dysfunction may initiate various intracellular signaling cascades, including phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinases (JNK), and mitogen-activated protein kinase (MAPK). Neuronal death, inflammation, neuronal excitation, mitochondrial malfunction, and protein deposition are all influenced by insulin. Recent research has focused on GLP-1 receptor agonists as a potential therapeutic target. They increase glucose-dependent insulin secretion and are beneficial in neurodegenerative diseases by reducing oxidative stress and cytokine production. They reduce the deposition of abnormal proteins by crossing the blood-brain barrier. The purpose of this article is to discuss the role of insulin dysfunction in the pathogenesis of neurological diseases, specifically dementia. Additionally, we reviewed the therapeutic target (GLP-1) and its receptor activators as a possible treatment of dementia.

Keywords:  GLP-1 activators; dementia; insulin signaling; neurodegeneration

DOI:  https://doi.org/10.2147/DNND.S247153
Autophagy. 2022 Mar 14. 1-14

Targeting lipophagy in macrophages improves repair in multiple sclerosis.

Mansour Haidar, Melanie Loix, Sam Vanherle, Tess Dierckx, Tim Vangansewinkel, Pascal Gervois, Esther Wolfs, Ivo Lambrichts, Jeroen F J Bogie, Jerome J A Hendriks.

  Foamy macrophages containing abundant intracellular myelin remnants are an important pathological hallmark of multiple sclerosis. Reducing the intracellular lipid burden in foamy macrophages is considered a promising therapeutic strategy to induce a phagocyte phenotype that promotes central nervous system repair. Recent research from our group showed that sustained intracellular accumulation of myelin-derived lipids skews these phagocytes toward a disease-promoting and more inflammatory phenotype. Our data now demonstrate that disturbed lipophagy, a selective form of autophagy that helps with the degradation of lipid droplets, contributes to the induction of this phenotype. Stimulating autophagy using the natural disaccharide trehalose reduced the lipid load and inflammatory phenotype of myelin-laden macrophages. Importantly, trehalose was able to boost remyelination in the ex vivo brain slice model and the in vivo cuprizone-induced demyelination model. In summary, our results provide a molecular rationale for impaired metabolism of myelin-derived lipids in macrophages, and identify lipophagy induction as a promising treatment strategy to promote remyelination.

Keywords:  Lipid droplets; lipophagy; multiple sclerosis; phagocyte; remyelination

DOI:  https://doi.org/10.1080/15548627.2022.2047343
Front Psychiatry. 2022 ;13 851679

N-Acetylcysteine Mitigates Social Dysfunction in a Rat Model of Autism Normalizing Glutathione Imbalance and the Altered Expression of Genes Related to Synaptic Function in Specific Brain Areas.

Sara Schiavi, Piergiorgio La Rosa, Sara Petrillo, Emilia Carbone, Jessica D'Amico, Fiorella Piemonte, Viviana Trezza.

  Prenatal exposure to valproic acid (VPA) is a risk factor for autism spectrum disorder (ASD) in humans and it induces autistic-like behaviors in rodents. Imbalances between GABAergic and glutamatergic neurotransmission and increased oxidative stress together with altered glutathione (GSH) metabolism have been hypothesized to play a role in both VPA-induced embriotoxicity and in human ASD. N-acetylcysteine (NAC) is an antioxidant precursor of glutathione and a modulator of glutamatergic neurotransmission that has been tested in ASD, although the clinical studies currently available provided controversial results. Here, we explored the effects of repeated NAC (150 mg/kg) administration on core autistic-like features and altered brain GSH metabolism in the VPA (500 mg/kg) rat model of ASD. Furthermore, we measured the mRNA expression of genes encoding for scaffolding and transcription regulation proteins, as well as the subunits of NMDA and AMPA receptors and metabotropic glutamate receptors mGLUR1 and mGLUR5 in brain areas that are relevant to ASD. NAC administration ameliorated the social deficit displayed by VPA-exposed rats in the three-chamber test, but not their stereotypic behavior in the hole board test. Furthermore, NAC normalized the altered GSH levels displayed by these animals in the hippocampus and nucleus accumbens, and it partially rescued the altered expression of post-synaptic terminal network genes found in VPA-exposed rats, such as NR2a, MGLUR5, GLUR1, and GLUR2 in nucleus accumbens, and CAMK2, NR1, and GLUR2 in cerebellum. These data indicate that NAC treatment selectively mitigates the social dysfunction displayed by VPA-exposed rats normalizing GSH imbalance and reestablishing the expression of genes related to synaptic function in a brain region-specific manner. Taken together, these data contribute to clarify the behavioral impact of NAC in ASD and the molecular mechanisms that underlie its effects.

Keywords:  N-acetylcysteine; autism; glutathione; rats; valproic acid

DOI:  https://doi.org/10.3389/fpsyt.2022.851679
J Cereb Blood Flow Metab. 2022 Mar 17. 271678X221089091

Astrocyte regulation of cerebral blood flow during hypoglycemia.

Amy R Nippert, Pei-Pei Chiang, Armani P Del Franco, Eric A Newman.

  Hypoglycemia triggers increases in cerebral blood flow (CBF), augmenting glucose supply to the brain. We have tested whether astrocytes, which can regulate vessel tone, contribute to this CBF increase. We hypothesized that hypoglycemia-induced adenosine signaling acts to increase astrocyte Ca2+ activity, which then causes the release of prostaglandins (PGs) and epoxyeicosatrienoic acids (EETs), leading to the dilation of brain arterioles and blood flow increases. We used an awake mouse model to investigate the effects of insulin-induced hypoglycemia on arterioles and astrocytes in the somatosensory cortex. During insulin-induced hypoglycemia, penetrating arterioles dilated and astrocyte Ca2+ signaling increased when blood glucose dropped below a threshold of ∼50 mg/dL. Application of the A2A adenosine receptor antagonist ZM-241385 eliminated hypoglycemia-evoked astrocyte Ca2+ increases and reduced arteriole dilations by 44% (p < 0.05). SC-560 and miconazole, which block the production of the astrocyte vasodilators PGs and EETs respectively, reduced arteriole dilations in response to hypoglycemia by 89% (p < 0.001) and 76% (p < 0.001). Hypoglycemia-induced arteriole dilations were decreased by 65% (p < 0.001) in IP3R2 knockout mice, which have reduced astrocyte Ca2+ signaling compared to wild-type. These results support the hypothesis that astrocytes contribute to hypoglycemia-induced increases in CBF by releasing vasodilators in a Ca2+-dependent manner.

Keywords:  Hypoglycemia; IP3R2 KO; adenosine; astrocytes; calcium signaling; cerebral blood flow

DOI:  https://doi.org/10.1177/0271678X221089091
ASN Neuro. 2022 Jan-Dec;14:14 17590914221087817

The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease.

Cory R Reiter, Rima Rebiai, Angelika Kwak, Jeff Marshall, Dylan Wozniak, Giusepe Scesa, Duc Nguyen, Emily Rue, Chandimal Pathmasiri, Robert Pijewski, Richard van Breemen, Stephanie Cologna, Stephen J Crocker, M Irene Givogri, Ernesto R Bongarzone.

  Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We evaluated the effects of attenuating EV secretion in the Twitcher brain by depleting ceramide production with an inhibitor of neutral sphingomyelinase 2, GW4869. Twitcher mice treated with GW4869 had decreased overall EV levels, reduced EV-associated psychosine and unexpectedly, correlated with increased disease severity. Notably, characterization of well-established, neuroanatomic hallmarks of disease pathology, such as demyelination and inflammatory gliosis, remained essentially unaltered in the brains of GW4869-treated Twitcher mice compared to vehicle-treated Twitcher controls. Further analysis of Twitcher brain pathophysiology is required to understand the mechanism behind early-onset disease severity in GW4869-treated mice. The results herein demonstrate that some pathogenic lipids like psychosine may be secreted using EV pathways. Our results highlight the relevance of this secretory mechanism as a possible contributor to spreading pathogenic lipids in neurological lipidoses.

Keywords:  demyelination; exosomes; extracellular vesicles; lysosomes; neurotoxicity; psychosine

DOI:  https://doi.org/10.1177/17590914221087817