bims-medebr 2022-08-14 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–08–14
sixteen papers selected by
Regina F. Fernández, Johns Hopkins University

Whole-brain neuronal MCT2 lactate transporter expression links metabolism to human brain structure and function.
Brain Energy Metabolism in Ischemic Stroke: Effects of Smoking and Diabetes.
Changes in regulators of lipid metabolism in the brain: a study of animal models of depression and hypothyroidism.
The Effect of the Ketogenic Diet on the Therapy of Neurodegenerative Diseases and Its Impact on Improving Cognitive Functions.
Location matters: hexokinase 1 in glucose metabolism and inflammation.
Effects of the administration of Elovl5-dependent fatty acids on a spino-cerebellar ataxia 38 mouse model.
Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.
Astrocyte-specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis.
Cholesterol 24-hydroxylase is a novel pharmacological target for anti-ictogenic and disease modification effects in epilepsy.
Natural fish oil improves the differentiation and maturation of oligodendrocyte precursor cells to oligodendrocytes in vitro after interaction with the blood-brain barrier.
An in vitro model of glucose transporter 1 deficiency syndrome at the blood-brain barrier using induced pluripotent stem cells.
Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System.
Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain.
Microglia-specific deletion of histone deacetylase 3 promotes inflammation resolution, white matter integrity, and functional recovery in a mouse model of traumatic brain injury.
The relationship between central fatigue and Attention Deficit/Hyperactivity Disorder of the inattentive type.
Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia.

Proc Natl Acad Sci U S A. 2022 Aug 16. 119(33): e2204619119

Whole-brain neuronal MCT2 lactate transporter expression links metabolism to human brain structure and function.

Vicente Medel, Nicolás Crossley, Ivana Gajardo, Eli Muller, L Felipe Barros, James M Shine, Jimena Sierralta.

  Brain activity is constrained by local availability of chemical energy, which is generated through compartmentalized metabolic processes. By analyzing data of whole human brain gene expression, we characterize the spatial distribution of seven glucose and monocarboxylate membrane transporters that mediate astrocyte-neuron lactate shuttle transfer of energy. We found that the gene coding for neuronal MCT2 is the only gene enriched in cerebral cortex where its abundance is inversely correlated with cortical thickness. Coexpression network analysis revealed that MCT2 was the only gene participating in an organized gene cluster enriched in K[Formula: see text] dynamics. Indeed, the expression of K[Formula: see text] subunits, which mediate lactate increases with spiking activity, is spatially coupled to MCT2 distribution. Notably, MCT2 expression correlated with fluorodeoxyglucose positron emission tomography task-dependent glucose utilization. Finally, the MCT2 messenger RNA gradient closely overlaps with functional MRI brain regions associated with attention, arousal, and stress. Our results highlight neuronal MCT2 lactate transporter as a key component of the cross-talk between astrocytes and neurons and a link between metabolism, cortical structure, and state-dependent brain function.

Keywords:  ANLS; brain metabolism; cognition; gene expression; monocarboxylate transporters

DOI:  https://doi.org/10.1073/pnas.2204619119
Int J Mol Sci. 2022 Jul 31. pii: 8512. [Epub ahead of print]23(15):

Brain Energy Metabolism in Ischemic Stroke: Effects of Smoking and Diabetes.

Ali Ehsan Sifat, Saeideh Nozohouri, Sabrina Rahman Archie, Ekram Ahmed Chowdhury, Thomas J Abbruscato.

  Proper regulation of energy metabolism in the brain is crucial for maintaining brain activity in physiological and different pathophysiological conditions. Ischemic stroke has a complex pathophysiology which includes perturbations in the brain energy metabolism processes which can contribute to worsening of brain injury and stroke outcome. Smoking and diabetes are common risk factors and comorbid conditions for ischemic stroke which have also been associated with disruptions in brain energy metabolism. Simultaneous presence of these conditions may further alter energy metabolism in the brain leading to a poor clinical prognosis after an ischemic stroke event. In this review, we discuss the possible effects of smoking and/or diabetes on brain glucose utilization and mitochondrial energy metabolism which, when present concurrently, may exacerbate energy metabolism in the ischemic brain. More research is needed to investigate brain glucose utilization and mitochondrial oxidative metabolism in ischemic stroke in the presence of smoking and/or diabetes, which would provide further insights on the pathophysiology of these comorbid conditions and facilitate the development of therapeutic interventions.

Keywords:  brain; diabetes; energy metabolism; ischemic stroke; smoking

DOI:  https://doi.org/10.3390/ijms23158512
Pharmacol Rep. 2022 Aug 11.

Changes in regulators of lipid metabolism in the brain: a study of animal models of depression and hypothyroidism.

Katarzyna Głombik, Jan Detka, Magdalena Kukla-Bartoszek, Alicja Maciejska, Bogusława Budziszewska.

  Metabolic disturbances in the brain are assumed to be early changes involved in the pathogenesis of depression, and these alterations may be intensified by a deficiency of thyroid hormones. In contrast to glucose metabolism, the link between altered brain lipids and the pathogenesis of depression is poorly understood, therefore in the present study, we determine transcription factors and enzymes regulating cholesterol and fatty acid biosynthesis in the brain structures in an animal model of depression, hypothyroidism and the coexistence of these diseases.In used model of depression, a decrease in the active form of the transcription factor SREBP-2 in the hippocampus was demonstrated, thus suggesting a reduction in cholesterol biosynthesis. In turn, in the hypothyroidism model, the reduction of cholesterol biosynthesis in the frontal cortex was demonstrated by both the reduction of mature SREBP-2 and the concentration of enzymes involved in cholesterol biosynthesis. The lower expression of LDL receptors in the frontal cortex indicates the restriction of cholesterol uptake into the cells in the model of coexistence of depression and hypothyroidism. Moreover, the identified changes in the levels of SNAP-25, GLP-1R and GLP-2R pointed to disturbances in synaptic plasticity and neuroprotection mechanisms in the examined brain structures.In conclusion, a reduction in cholesterol synthesis in the hippocampus in the model of depression may be the reason for the reduction of synaptic plasticity, whereas a lower level of LDL-R occurring in the frontal cortex in rats from the model of depression and hypothyroidism coexistence could be the reason of anxiogenic and depression-like behaviors.

Keywords:  Brain lipid biosynthesis; Cholesterol; Depression; Fatty acids; Hypothyroidism

DOI:  https://doi.org/10.1007/s43440-022-00395-8
Dement Geriatr Cogn Dis Extra. 2022 May-Aug;12(2):12(2): 100-106

The Effect of the Ketogenic Diet on the Therapy of Neurodegenerative Diseases and Its Impact on Improving Cognitive Functions.

Klaudia Grochowska, Anna Przeliorz.

  The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with controlled amounts of protein. The use of drastic caloric restriction or ultralow-carbohydrate diets increases the production of ketone bodies, which are an alternative energy substrate in situations of insufficient glucose supply. Alzheimer's disease (AD) and Parkinson's disease are the most common neurodegenerative diseases in the world. It is believed that carbohydrate metabolism disorders may affect the progression of these diseases, as confirmed by both animal and human studies. Among patients with AD, the presence of ketone bodies in the body can improve cerebral circulation. Among Parkinson's patients, the presence of ketone bodies can reduce muscle tremor and stiffness, as well as improve cognitive function. The results of the research indicate that using a low-carbohydrate diet, including a KD, may have a beneficial effect on brain function in diseases that cause neuronal damage.

Keywords:  Alzheimer's disease; Ketogenic diet; Neurodegenerative diseases; Parkinson's disease

DOI:  https://doi.org/10.1159/000524331
Trends Endocrinol Metab. 2022 Aug 08. pii: S1043-2760(22)00140-0. [Epub ahead of print]

Location matters: hexokinase 1 in glucose metabolism and inflammation.

Sivaraj M Sundaram, Luke A Doughty, Michael W Sereda.

  Hexokinase (HK)-1 mitochondrial-binding mechanisms and consequential physiological relevance remain unclear. Recently, De Jesus et al. studied myeloid cells with HK1 carrying mutated mitochondrial-binding domains (MBDs) and provided evidence that HK1 localization controls glucose metabolic fate. Increases in cytosolic HK1 may also contribute to the inflammation associated with diabetes and aging.

Keywords:  aging; deacetylation; diabetes; glucose metabolism; inflammation; nitrosylation

DOI:  https://doi.org/10.1016/j.tem.2022.07.005
Behav Brain Funct. 2022 Aug 06. 18(1): 8

Effects of the administration of Elovl5-dependent fatty acids on a spino-cerebellar ataxia 38 mouse model.

Ilaria Balbo, Francesca Montarolo, Federica Genovese, Filippo Tempia, Eriola Hoxha.

   BACKGROUND: Spinocerebellar ataxia 38 (SCA38) is a rare autosomal neurological disorder characterized by ataxia and cerebellar atrophy. SCA38 is caused by mutations of ELOVL5 gene. ELOVL5 gene encodes a protein, which elongates long chain polyunsaturated fatty acids (PUFAs). Knockout mice lacking Elovl5 recapitulate SCA38 symptoms, including motor coordination impairment and disruption of cerebellar architecture. We asked whether, in Elovl5 knockout mice (Elovl5-/-), a diet with both ω3 and ω6 PUFAs downstream Elovl5 can prevent the development of SCA38 symptoms, and at which age such treatment is more effective. Elovl5-/- mice were fed either with a diet without or containing PUFAs downstream the Elovl5 enzyme, starting at different ages. Motor behavior was assessed by the balance beam test and cerebellar structure by morphometric analysis.
RESULTS: The administration from birth of the diet containing PUFAs downstream Elovl5 led to a significant amelioration of the motor performance in the beam test of Elovl5-/- mice, with a reduction of foot slip errors at 6 months from 2.2 ± 0.3 to 1.3 ± 0.2 and at 8 months from 3.1 ± 0.5 to 1.9 ± 0.3. On the contrary, administration at 1 month of age or later had no effect on the motor impairment. The cerebellar Purkinje cell layer and the white matter area of Elovl5-/ -mice were not rescued even by the administration of diet from birth, suggesting that the improvement of motor performance in the beam test was due to a functional recovery of the cerebellar circuitry.
CONCLUSIONS: These results suggest that the dietary intervention in SCA38, whenever possible, should be started from birth or as early as possible.

Keywords:  Elovl5; Motor deficits; Polyunsaturated fatty acids; SCA38; Spino-cerebellar ataxia

DOI:  https://doi.org/10.1186/s12993-022-00194-4
Mol Cell. 2022 Aug 09. pii: S1097-2765(22)00647-5. [Epub ahead of print]

Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.

Consuelo Torrini, Trang Thi Thu Nguyen, Chang Shu, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Erin Heather Seeley, Guoan Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin.

  Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-13C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM.

Keywords:  ATAC-seq; ChIP-seq; glioblastoma; lactate; metabolic flux analysis; tumor metabolism

DOI:  https://doi.org/10.1016/j.molcel.2022.06.030
Glia. 2022 Aug 10.

Astrocyte-specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis.

Shuang-Feng Xu, Zhong-Qiu Pang, Yong-Gang Fan, Yan-Hui Zhang, Yu-Han Meng, Chen-Yang Bai, Meng-Yu Jia, Yan-Hong Chen, Zhan-You Wang, Chuang Guo.

  Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte-specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the primary astrocytes led to decreased sterol regulatory element binding protein 2 (Srebp2) activation and cholesterol production, and cholesterol content in cKO mice and/or in astrocytes was restored by exogenous Lf or a Srebp2 agonist. Moreover, neuronal dendritic complexity and total dendritic length were decreased after culture with the culture medium of the primary astrocytes derived from cKO mice and that this decrease was reversed after cholesterol supplementation. Alternatively, these alterations were associated with an activation of AMP-activated protein kinase (AMPK) and inhibition of SREBP2 nuclear translocation. These data suggest that astrocytic Lf might directly or indirectly control in situ cholesterol synthesis, which may be implicated in neurodevelopment and several neurological diseases.

Keywords:  AMP-activated protein kinase; Lactoferrin; astrocyte; cholesterol; sterol regulatory element binding protein 2

DOI:  https://doi.org/10.1002/glia.24259
Neurobiol Dis. 2022 Aug 03. pii: S0969-9961(22)00227-3. [Epub ahead of print] 105835

Cholesterol 24-hydroxylase is a novel pharmacological target for anti-ictogenic and disease modification effects in epilepsy.

Alessia Salamone, Gaetano Terrone, Rossella Di Sapia, Silvia Balosso, Teresa Ravizza, Luca Beltrame, Ilaria Craparotta, Laura Mannarino, Sara Raimondi Cominesi, Massimo Rizzi, Alberto Pauletti, Sergio Marchini, Luca Porcu, Till S Zimmer, Eleonora Aronica, Matthew During, Brett Abrahams, Shinichi Kondo, Toshiya Nishi, Annamaria Vezzani.

  Therapies for epilepsy mainly provide symptomatic control of seizures since most of the available drugs do not target disease mechanisms. Moreover, about one-third of patients fail to achieve seizure control. To address the clinical need for disease-modifying therapies, research should focus on targets which permit interventions finely balanced between optimal efficacy and safety. One potential candidate is the brain-specific enzyme cholesterol 24-hydroxylase. This enzyme converts cholesterol to 24S-hydroxycholesterol, a metabolite which among its biological roles modulates neuronal functions relevant for hyperexcitability underlying seizures. To study the role of cholesterol 24-hydroxylase in epileptogenesis, we administered soticlestat (TAK-935/OV935), a potent and selective brain-penetrant inhibitor of the enzyme, during the early disease phase in a mouse model of acquired epilepsy using a clinically relevant dose. During soticlestat treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased by about 3-fold compared to vehicle-treated mice, as assessed by EEG monitoring. Notably, the therapeutic effect was maintained 6.5 weeks after drug wash-out when seizure number was reduced by about 4-fold and their duration by 2-fold. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells as assessed by post-mortem brain histology. High throughput RNA-sequencing of hippocampal neurons and glia in mice treated with soticlestat during epileptogenesis showed that inhibition of cholesterol 24-hydroxylase did not directly affect the epileptogenic transcriptional network, but rather modulated a non-overlapping set of genes that might oppose the pathogenic mechanisms of the disease. In human temporal lobe epileptic foci, we determined that cholesterol 24-hydroxylase expression trends higher in neurons, similarly to epileptic mice, while the enzyme is ectopically induced in astrocytes compared to control specimens. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy. Data show that cholesterol 24-hydroxylase contributes to spontaneous seizures and is involved in disease progression, thus it represents a novel target for chronic seizures inhibition and disease-modification therapy in epilepsy.

Keywords:  Epileptogenesis; Glia; Neuroprotection; Status epilepticus; Temporal lobe epilepsy

DOI:  https://doi.org/10.1016/j.nbd.2022.105835
Front Immunol. 2022 ;13 932383

Natural fish oil improves the differentiation and maturation of oligodendrocyte precursor cells to oligodendrocytes in vitro after interaction with the blood-brain barrier.

Paweł Piatek, Natalia Lewkowicz, Sylwia Michlewska, Marek Wieczorek, Radosław Bonikowski, Karol Parchem, Przemysław Lewkowicz, Magdalena Namiecinska.

  The blood-brain barrier (BBB) tightly controls the microenvironment of the central nervous system (CNS) to allow neurons to function properly. Additionally, emerging studies point to the beneficial effect of natural oils affecting a wide variety of physiological and pathological processes in the human body. In this study, using an in vitro model of the BBB, we tested the influence of natural fish oil mixture (FOM) vs. borage oil (BO), both rich in long-chain polyunsaturated fatty acids (LC-PUFAs) and monounsaturated fatty acids (MUFAs) such as oleic acid (C18:1n9c) or nervonic acid (NA), on human oligodendrocyte precursor cells (hOPCs) during their maturation to oligodendrocytes (OLs) regarding their ability to synthesize myelin peptides and NA. We demonstrated that FOM, opposite to BO, supplemented endothelial cells (ECs) and astrocytes forming the BBB, affecting the function of hOPCs during their maturation. This resulted in improved synthesis of myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), and NA in mature OLs. This effect is probably the result of BBB cell and hOPC stimulation via free fatty acid receptors (FFARs), which increases insulin growth factor-1 (IGF-1), ciliary neurotrophic factor (CNTF), and brain-derived neurotrophic factor (BDNF) and inhibits fibroblast growth factor 2 (FGF-2) synthesis. The unique formula of fish oil, characterized by much more varied components compared to those of BOs, also improved the enhancement of the tight junction by increasing the expression of claudin-5 and VE-cadherin on ECs. The obtained data justify consideration of naturally derived fish oil intake in human diet as affecting during remyelination.

Keywords:  Blood-brain barrier; astrocytes; endothelial cells; long-chain fatty acids; oligodendrocyte precursor cells; oligodendrocytes; remyelinating therapy

DOI:  https://doi.org/10.3389/fimmu.2022.932383
J Neurochem. 2022 Aug 09.

An in vitro model of glucose transporter 1 deficiency syndrome at the blood-brain barrier using induced pluripotent stem cells.

Iqra Pervaiz, Fatema Tuz Zahra, Constantinos Mikelis, Abraham Jacob Al-Ahmad.

  Glucose is an important source of energy for the central nervous system. Its uptake at the blood-brain barrier (BBB) is mostly mediated via glucose transporter 1 (GLUT1), a facilitated transporter encoded by the SLC2A1 gene. GLUT1 Deficiency Syndrome (GLUT1DS) is a haploinsufficiency characterized by mutations in the SLC2A1 gene, resulting in impaired glucose uptake at the BBB and clinically characterized by epileptic seizures and movement disorder. A major limitation is an absence of in vitro models of the BBB reproducing the disease. This study aimed to characterize an in vitro model of GLUT1DS using human pluripotent stem cells (iPSCs). Two GLUT1DS clones were generated (GLUT1-iPSC) from their original parental clone iPS(IMR90)-c4 by CRISPR/Cas9 and differentiated into brain microvascular endothelial cells (iBMECs). Cells were characterized in terms of SLC2A1 expression, changes in the barrier function, glucose uptake and metabolism, and angiogenesis. GLUT1DS iPSCs and iBMECs showed comparable phenotype to their parental control, with exception of reduced GLUT1 expression at the protein level. Although no major disruption in the barrier function was reported in the two clones, a significant reduction in glucose uptake accompanied by an increase in glycolysis and mitochondrial respiration was reported in both GLUT1DS-iBMECs. Finally, impaired angiogenic features were reported in such clones compared to the parental clone. Our study provides the first documented characterization of GLUT1DS-iBMECs generated by CRISPR-Cas9, suggesting that GLUT1 truncation appears detrimental to brain angiogenesis and brain endothelial bioenergetics, but maybe not be detrimental to iBMECs differentiation and barriergenesis. Our future direction is to further characterize the functional outcome of such truncated product, as well as its impact on other cells of the neurovascular unit.

Keywords:  Blood-brain barrier; GLUT1; GLUT1 deficiency syndrome; induced pluripotent stem cells

DOI:  https://doi.org/10.1111/jnc.15684
Int J Mol Sci. 2022 Aug 04. pii: 8683. [Epub ahead of print]23(15):

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System.

Daniela Passarella, Maurizio Ronci, Valentina Di Liberto, Mariachiara Zuccarini, Giuseppa Mudò, Carola Porcile, Monica Frinchi, Patrizia Di Iorio, Henning Ulrich, Claudio Russo.

  Recent studies have highlighted the mechanisms controlling the formation of cerebral cholesterol, which is synthesized in situ primarily by astrocytes, where it is loaded onto apolipoproteins and delivered to neurons and oligodendrocytes through interactions with specific lipoprotein receptors. The "cholesterol shuttle" is influenced by numerous proteins or carbohydrates, which mainly modulate the lipoprotein receptor activity, function and signaling. These molecules, provided with enzymatic/proteolytic activity leading to the formation of peptide fragments of different sizes and specific sequences, could be also responsible for machinery malfunctions, which are associated with neurological, neurodegenerative and neurodevelopmental disorders. In this context, we have pointed out that purines, ancestral molecules acting as signal molecules and neuromodulators at the central nervous system, can influence the homeostatic machinery of the cerebral cholesterol turnover and vice versa. Evidence gathered so far indicates that purine receptors, mainly the subtypes P2Y2, P2X7 and A2A, are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's and Niemann-Pick C diseases, by controlling the brain cholesterol homeostasis; in addition, alterations in cholesterol turnover can hinder the purine receptor function. Although the precise mechanisms of these interactions are currently poorly understood, the results here collected on cholesterol-purine reciprocal control could hopefully promote further research.

Keywords:  LDL receptors; cholesterol; purinergic receptors

DOI:  https://doi.org/10.3390/ijms23158683
Int J Mol Sci. 2022 Jul 27. pii: 8274. [Epub ahead of print]23(15):

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain.

Jinxuan Ren, Jiaqi Lin, Lina Yu, Min Yan.

  The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G protein-coupled signaling receptors, Toll-like receptors, and ion channels to activate several second messengers. Lysophosphatidylcholine (LPC) is increasingly considered a key marker/factor positively in pathological states, especially inflammation and atherosclerosis development. Current studies have indicated that the injury of nervous tissues promotes oxidative stress and lipid peroxidation, as well as excessive accumulation of LPC, enhancing the membrane hyperexcitability to induce chronic pain, which may be recognized as one of the hallmarks of chronic pain. However, findings from lipidomic studies of LPC have been lacking in the context of chronic pain. In this review, we focus in some detail on LPC sources, biochemical pathways, and the signal-transduction system. Moreover, we outline the detection methods of LPC for accurate analysis of each individual LPC species and reveal the pathophysiological implication of LPC in chronic pain, which makes it an interesting target for biomarkers and the development of medicine regarding chronic pain.

Keywords:  G protein-coupled receptors; Toll-like receptors; biomarkers; chronic pain; ion channels; lipidomics; lysophosphatidylcholine; metabolism

DOI:  https://doi.org/10.3390/ijms23158274
J Neuroinflammation. 2022 Aug 06. 19(1): 201

Microglia-specific deletion of histone deacetylase 3 promotes inflammation resolution, white matter integrity, and functional recovery in a mouse model of traumatic brain injury.

Yongfang Zhao, Hongfeng Mu, Yichen Huang, Sicheng Li, Yangfan Wang, R Anne Stetler, Michael V L Bennett, C Edward Dixon, Jun Chen, Yejie Shi.

   BACKGROUND: Histone deacetylases (HDACs) are believed to exacerbate traumatic brain injury (TBI) based on studies using pan-HDAC inhibitors. However, the HDAC isoform responsible for the detrimental effects and the cell types involved remain unknown, which may hinder the development of specific targeting strategies that boost therapeutic efficacy while minimizing side effects. Microglia are important mediators of post-TBI neuroinflammation and critically impact TBI outcome. HDAC3 was reported to be essential to the inflammatory program of in vitro cultured macrophages, but its role in microglia and in the post-TBI brain has not been investigated in vivo.
METHODS: We generated HDAC3LoxP mice and crossed them with CX3CR1CreER mice, enabling in vivo conditional deletion of HDAC3. Microglia-specific HDAC3 knockout (HDAC3 miKO) was induced in CX3CR1CreER:HDAC3LoxP mice with 5 days of tamoxifen treatment followed by a 30-day development interval. The effects of HDAC3 miKO on microglial phenotype and neuroinflammation were examined 3-5 days after TBI induced by controlled cortical impact. Neurological deficits and the integrity of white matter were assessed for 6 weeks after TBI by neurobehavioral tests, immunohistochemistry, electron microscopy, and electrophysiology.
RESULTS: HDAC3 miKO mice harbored specific deletion of HDAC3 in microglia but not in peripheral monocytes. HDAC3 miKO reduced the number of microglia by 26%, but did not alter the inflammation level in the homeostatic brain. After TBI, proinflammatory microglial responses and brain inflammation were markedly alleviated by HDAC3 miKO, whereas the infiltration of blood immune cells was unchanged, suggesting a primary effect of HDAC3 miKO on modulating microglial phenotype. Importantly, HDAC3 miKO was sufficient to facilitate functional recovery for 6 weeks after TBI. TBI-induced injury to axons and myelin was ameliorated, and signal conduction by white matter fiber tracts was significantly enhanced in HDAC3 miKO mice.
CONCLUSION: Using a novel microglia-specific conditional knockout mouse model, we delineated for the first time the role of microglial HDAC3 after TBI in vivo. HDAC3 miKO not only reduced proinflammatory microglial responses, but also elicited long-lasting improvement of white matter integrity and functional recovery after TBI. Microglial HDAC3 is therefore a promising therapeutic target to improve long-term outcomes after TBI.

Keywords:  Conditional gene knockout; Controlled cortical impact; HDAC3; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-022-02563-2
Neurochem Res. 2022 Aug 11.

The relationship between central fatigue and Attention Deficit/Hyperactivity Disorder of the inattentive type.

Takanobu Yamamoto.

  Chronic fatigue and central fatigue with malaise significantly impair quality of life. Inattention caused by central fatigue is closely related to attention deficit/hyperactivity disorder (ADHD) symptoms, but the neurochemical mechanism of central fatigue remains hypothetical. The serotonin hypothesis of central fatigue was proposed first, serving as the central dogma for the molecular and neural mechanisms of central fatigue, and underpinning many studies. The tryptophan hypothesis was proposed because tryptophan released into the synaptic cleft of neurons in the brain coincides with and responds sensitively to development of fatigue. Tryptophan is highly bioactive, with brain concentrations of 50 to 200 times that of serotonin. The tryptophan-kynurenic acid-synergy hypothesis posits that central fatigue is not monocausal but a synergistic effect between tryptophan itself and its catabolite kynurenic acid. Central fatigue is associated with mental health problems and is a cause of inattention, thereby warranting scrutiny for its relationship with ADHD. Fatigability in ADHD is mediated by tryptophan, in which abnormal enhancement of the tryptophan-kynurenine-kynurenic acid pathway causes an imbalance in monoamine nervous system function. Notably, noradrenergic neuronal dysfunction is associated with the characteristic inattention of ADHD. Neutral amino acids such as branched-chain amino acids (BCAAs) can assist recovery from attentional and cognitive decline caused by central fatigue. Since they are transported by the same L-amino acid transporter as tryptophan, BCAAs compete with tryptophan to inhibit its brain uptake. Controlling central fatigue this way may improve attentional cognitive performance.

Keywords:  ADHD; BCAAs; Central fatigue; Kynurenic acid; Monoamine; Tryptophan

DOI:  https://doi.org/10.1007/s11064-022-03693-y
Elife. 2022 Aug 09. pii: e76451. [Epub ahead of print]11

Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia.

Lauritz Kennedy, Emilie R Glesaaen, Vuk Palibrk, Marco Pannone, Wei Wang, Ali Al-Jabri, Rajikala Suganthan, Niklas Meyer, Marie Landa Austbø, Xiaolin Lin, Linda H Bergersen, Magnar Bjørås, Johanne E Rinholm.

  Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI may aid the development of better treatments. Here, we study the role of lactate receptor HCAR1 in tissue repair after neonatal HI in mice. We show that HCAR1 knockout mice have reduced tissue regeneration compared with wildtype mice. Furthermore, proliferation of neural progenitor cells and glial cells, as well as microglial activation was impaired. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of wildtype mice involving about 7300 genes. In contrast, the HCAR1 knockout mice showed a modest response, involving about 750 genes. Notably, fundamental processes in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 knockout. Our data suggest that HCAR1 is a key transcriptional regulator of pathways that promote tissue regeneration after HI.

Keywords:  cell biology; gpr81; hca1; hcar1; ischemia; lactate; mouse; neurogenesis; neuroscience

DOI:  https://doi.org/10.7554/eLife.76451