bims-medebr 2023-12-10 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒12‒10
fifteen papers selected by
Regina F. Fernández, Johns Hopkins University

Brain Lipids and Lipid Droplet Dysregulation in Alzheimer's Disease and Neuropsychiatric Disorders.
Synthesis and Preclinical Evaluation of 22-[18F]Fluorodocosahexaenoic Acid as a Positron Emission Tomography Probe for Monitoring Brain Docosahexaenoic Acid Uptake Kinetics.
Brain apolipoprotein E levels in mice challenged by a Western diet increase in an allele-dependent manner.
Fragmentation of functional resting state brain networks in a transgenic mouse model of tau pathology: A metabolic connectivity study using [18F]FDG-PET.
Metabolic energetics underlying attractors in neural models.
White matter injury across neurodegenerative disease.
Rethinking neurodegenerative diseases: neurometabolic concept linking lipid oxidation to diseases in the central nervous system.
Fatty acid binding protein type 7 deficiency preserves auditory function in noise-exposed mice.
An ex vivo screening using mouse brain mitochondria identified seco-cycline D as an inhibitor of mitochondrial permeability transition pore.
Astrocytes produce nitric oxide via nitrite reduction in mitochondria to regulate cerebral blood flow during brain hypoxia.
A new role for phosphoinositides in regulating mitochondrial dynamics.
An unusually mild case of biotin-thiamine-responsive basal ganglia disease.
Temporal gene expression changes and affected pathways in neurodevelopment of a mouse model of Smith-Lemli-Opitz syndrome.
Quantification of cytosine modifications in the aged mouse brain.
A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence.

Complex Psychiatry. 2023 Jan-Dec;9(1-4):9(1-4): 154-171

Brain Lipids and Lipid Droplet Dysregulation in Alzheimer's Disease and Neuropsychiatric Disorders.

Xiaojie Zhao, Siwei Zhang, Alan R Sanders, Jubao Duan.

  Background: Lipids are essential components of the structure and for the function of brain cells. The intricate balance of lipids, including phospholipids, glycolipids, cholesterol, cholesterol ester, and triglycerides, is crucial for maintaining normal brain function. The roles of lipids and lipid droplets and their relevance to neurodegenerative and neuropsychiatric disorders (NPDs) remain largely unknown.Summary: Here, we reviewed the basic role of lipid components as well as a specific lipid organelle, lipid droplets, in brain function, highlighting the potential impact of altered lipid metabolism in the pathogenesis of Alzheimer's disease (AD) and NDPs.
Key Messages: Brain lipid dysregulation plays a pivotal role in the pathogenesis and progression of neurodegenerative and NPDs including AD and schizophrenia. Understanding the cell type-specific mechanisms of lipid dysregulation in these diseases is crucial for identifying better diagnostic biomarkers and for developing therapeutic strategies aiming at restoring lipid homeostasis.

Keywords:  Alzheimer’s disease; Cholesterol; Dysfunction; Lipid droplets; Lipids; Neuropsychiatric disorders; Schizophrenia

DOI:  https://doi.org/10.1159/000535131
ACS Chem Neurosci. 2023 Dec 04.

Synthesis and Preclinical Evaluation of 22-[18F]Fluorodocosahexaenoic Acid as a Positron Emission Tomography Probe for Monitoring Brain Docosahexaenoic Acid Uptake Kinetics.

Marlon Vincent V Duro, Juno Van Valkenburgh, Diana E Ingles, Jenny Tran, Zhiheng Cai, Brandon Ebright, Shaowei Wang, Bilal E Kerman, Jasmin Galvan, Sung Hee Hwang, Naomi S Sta Maria, Francesca Zanderigo, Etienne Croteau, Stephen C Cunnane, Stanley I Rapoport, Stan G Louie, Russell E Jacobs, Hussein N Yassine, Kai Chen.

  Docosahexaenoic acid [22:6(n-3), DHA], a polyunsaturated fatty acid, has an important role in regulating neuronal functions and in normal brain development. Dysregulated brain DHA uptake and metabolism are found in individuals carrying the APOE4 allele, which increases the genetic risk for Alzheimer's disease (AD), and are implicated in the progression of several neurodegenerative disorders. However, there are limited tools to assess brain DHA kinetics in vivo that can be translated to humans. Here, we report the synthesis of an ω-radiofluorinated PET probe of DHA, 22-[18F]fluorodocosahexaenoic acid (22-[18F]FDHA), for imaging the uptake of DHA into the brain. Using the nonradiolabeled 22-FDHA, we confirmed that fluorination of DHA at the ω-position does not significantly alter the anti-inflammatory effect of DHA in microglial cells. Through dynamic PET-MR studies using mice, we observed the accumulation of 22-[18F]FDHA in the brain over time and estimated DHA's incorporation coefficient (K*) using an image-derived input function. Finally, DHA brain K* was validated using intravenous administration of 15 mg/kg arecoline, a natural product known to increase the DHA K* in rodents. 22-[18F]FDHA is a promising PET probe that can reveal altered lipid metabolism in APOE4 carriers, AD, and other neurologic disorders. This new probe, once translated into humans, would enable noninvasive and longitudinal studies of brain DHA dynamics by guiding both pharmacological and nonpharmacological interventions for neurodegenerative diseases.

Keywords:  docosahexaenoic acid; incorporation coefficient; polyunsaturated fatty acid; positron emission tomography; radiofluorination

DOI:  https://doi.org/10.1021/acschemneuro.3c00681
Aging Brain. 2023 ;4 100102

Brain apolipoprotein E levels in mice challenged by a Western diet increase in an allele-dependent manner.

Braison Liemisa, Samantha F Newbury, Mariah J Novy, Jonathan A Pasato, Jose Morales-Corraliza, Katherine Y Peng, Paul M Mathews.

  Human apolipoprotein E (APOE) is the greatest determinant of genetic risk for memory deficits and Alzheimer's disease (AD). While APOE4 drives memory loss and high AD risk, APOE2 leads to healthy brain aging and reduced AD risk compared to the common APOE3 variant. We examined brain APOE protein levels in humanized mice homozygous for these alleles and found baseline levels to be age- and isoform-dependent: APOE2 levels were greater than APOE3, which were greater than APOE4. Despite the understanding that APOE lipoparticles do not traverse the blood-brain barrier, we show that brain APOE levels are responsive to dietary fat intake. Challenging mice for 6 months on a Western diet high in fat and cholesterol increased APOE protein levels in an allele-dependent fashion with a much greater increase within blood plasma than within the brain. In the brain, APOE2 levels responded most to the Western diet challenge, increasing by 20 % to 30 %. While increased lipoparticles are generally deleterious in the periphery, we propose that higher brain APOE2 levels may represent a readily available pool of beneficial lipid particles for neurons.

Keywords:  Alzheimer’s disease; Apolipoprotein E; Regular diet; Western diet

DOI:  https://doi.org/10.1016/j.nbas.2023.100102
Exp Neurol. 2023 Dec 03. pii: S0014-4886(23)00317-5. [Epub ahead of print] 114632

Fragmentation of functional resting state brain networks in a transgenic mouse model of tau pathology: A metabolic connectivity study using [18F]FDG-PET.

Heike Endepols, Marta Anglada-Huguet, Eckhard Mandelkow, Bernd Neumaier, Eva-Maria Mandelkow, Alexander Drzezga.

  In a previous study, regional reductions in cerebral glucose metabolism have been demonstrated in the tauopathy mouse model rTg4510 (Endepols et al., 2022). Notably, glucose hypometabolism was present in some brain regions without co-localized synaptic degeneration measured with [18F]UCB-H. We hypothesized that in those regions hypometabolism may reflect reduced functional connectivity rather than synaptic damage. To test this hypothesis, we performed seed-based metabolic connectivity analyses using [18F]FDG-PET data in this mouse model. Eight rTg4510 mice at the age of seven months and 8 non-transgenic littermates were injected intraperitoneally with 11.1 ± 0.8 MBq [18F]FDG and spent a 35-min uptake period awake in single cages. Subsequently, they were anesthetized and measured in a small animal PET scanner for 30 min. Three seed-based connectivity analyses were performed per group. Seeds were selected for apparent mismatch between [18F]FDG and [18F]UCB-H. A seed was placed either in the medial orbitofrontal cortex, dorsal hippocampus or dorsal thalamus, and correlated with all other voxels of the brain across animals. In the control group, the emerging correlative pattern was strongly overlapping for all three seed locations, indicating a uniform fronto-thalamo-hippocampal resting state network. In contrast, rTg4510 mice showed three distinct networks with minimal overlap. Frontal and thalamic networks were greatly diminished. The hippocampus, however, formed a new network with the whole parietal cortex. We conclude that resting-state functional networks are fragmented in the brain of rTg4510 mice. Thus, hypometabolism can be explained by reduced functional connectivity of brain areas devoid of tau-related pathology, such as the thalamus.

Keywords:  Metabolic connectivity; Small animal PET; Tauopathy mouse model

DOI:  https://doi.org/10.1016/j.expneurol.2023.114632
J Neurophysiol. 2023 Dec 06.

Metabolic energetics underlying attractors in neural models.

Richard B Buxton, Eric C Wong.

  Neural population modeling, including the role of neural attractors, is a promising tool for understanding many aspects of brain function. We propose a modeling framework to connect the abstract variables used in modeling to recent cellular level estimates of the bioenergetic costs of different aspects of neural activity, measured in ATP consumed per second per neuron. Based on recent work, an empirical reference for brain ATP use for the awake resting brain was estimated as ~2x109 ATP/s-neuron across several mammalian species. The energetics framework was applied to the Wilson-Cowan (WC) model of two interacting populations of neurons, one excitatory (E) and one inhibitory (I). Attractors were considered exhibiting steady-state behavior and limit cycle behavior, both of which end when the excitatory stimulus ends, and sustained activity that persists after the stimulus ends. The energy cost of limit cycles, with oscillations much faster than the average neuronal firing rate of the population, track more closely with the firing rate than the limit cycle frequency. Self-sustained firing driven by recurrent excitation, though, involves higher firing rates and a higher energy cost. As an example of a simple network in which each node is a WC model, a combination of three nodes can serve as a flexible circuit element that turns on with an oscillating output when input passes a threshold and then persists after the input ends (an 'on-switch'), with moderate overall ATP use. The proposed framework can serve as a guide for anchoring neural population models to plausible bioenergetics requirements.

Keywords:  Wilson-Cowan model; brain energy metabolism; cerebral metabolic rate of oxygen (CMRO2); neural population models

DOI:  https://doi.org/10.1152/jn.00120.2023
Trends Neurosci. 2023 Dec 04. pii: S0166-2236(23)00263-1. [Epub ahead of print]

White matter injury across neurodegenerative disease.

Lindsay K Festa, Judith B Grinspan, Kelly L Jordan-Sciutto.

  Oligodendrocytes (OLs), the myelin-generating cells of the central nervous system (CNS), are active players in shaping neuronal circuitry and function. It has become increasingly apparent that injury to cells within the OL lineage plays a central role in neurodegeneration. In this review, we focus primarily on three degenerative disorders in which white matter loss is well documented: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We discuss clinical data implicating white matter injury as a key feature of these disorders, as well as shared and divergent phenotypes between them. We examine the cellular and molecular mechanisms underlying the alterations to OLs, including chronic neuroinflammation, aggregation of proteins, lipid dysregulation, and organellar stress. Last, we highlight prospects for therapeutic intervention targeting the OL lineage to restore function.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; lipid dysregulation; neuroinflammation; organellar stress

DOI:  https://doi.org/10.1016/j.tins.2023.11.003
Neural Regen Res. 2024 Jul 01. 19(7): 1437-1445

Rethinking neurodegenerative diseases: neurometabolic concept linking lipid oxidation to diseases in the central nervous system.

Steinunn Sara Helgudóttir, Anne Skøttrup Mørkholt, Jacek Lichota, Preben Bruun-Nyzell, Mads Christian Andersen, Nanna Marie Juhl Kristensen, Amanda Krøger Johansen, Mikela Reinholdt Zinn, Hulda Maria Jensdóttir, John Dirk Vestergaard Nieland.

ABSTRACT: Currently, there is a lack of effective medicines capable of halting or reversing the progression of neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, or Alzheimer's disease. Given the unmet medical need, it is necessary to reevaluate the existing paradigms of how to target these diseases. When considering neurodegenerative diseases from a systemic neurometabolic perspective, it becomes possible to explain the shared pathological features. This innovative approach presented in this paper draws upon extensive research conducted by the authors and researchers worldwide. In this review, we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases. We provide an overview of the risk factors associated with developing neurodegenerative disorders, including genetic, epigenetic, and environmental factors. Additionally, we examine pathological mechanisms implicated in these diseases such as oxidative stress, accumulation of misfolded proteins, inflammation, demyelination, death of neurons, insulin resistance, dysbiosis, and neurotransmitter disturbances. Finally, we outline a proposal for the restoration of mitochondrial metabolism, a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.

DOI: https://doi.org/10.4103/1673-5374.387965
Sci Rep. 2023 Dec 06. 13(1): 21494

Fatty acid binding protein type 7 deficiency preserves auditory function in noise-exposed mice.

Jun Suzuki, Tomotaka Hemmi, Masamitsu Maekawa, Masahiro Watanabe, Hitoshi Inada, Hiroyuki Ikushima, Tetsuya Oishi, Ryoukichi Ikeda, Yohei Honkura, Yoshiteru Kagawa, Tetsuaki Kawase, Nariyasu Mano, Yuji Owada, Noriko Osumi, Yukio Katori.

Fatty acid-binding protein 7 (FABP7) is vital for uptake and trafficking of fatty acids in the nervous system. To investigate the involvement of FABP7 in noise-induced hearing loss (NIHL) pathogenesis, we used Fabp7 knockout (KO) mice generated via CRISPR/Cas9 in the C57BL/6 background. Initial auditory brainstem response (ABR) measurements were conducted at 9 weeks, followed by noise exposure at 10 weeks. Subsequent ABRs were performed 24 h later, with final measurements at 12 weeks. Inner ears were harvested 24 h after noise exposure for RNA sequencing and metabolic analyses. We found no significant differences in initial ABR measurements, but Fabp7 KO mice showed significantly lower thresholds in the final ABR measurements. Hair cell survival was also enhanced in Fabp7 KO mice. RNA sequencing revealed that genes associated with the electron transport chain were upregulated or less impaired in Fabp7 KO mice. Metabolomic analysis revealed various alterations, including decreased glutamate and aspartate in Fabp7 KO mice. In conclusion, FABP7 deficiency mitigates cochlear damage following noise exposure. This protective effect was supported by the changes in gene expression of the electron transport chain, and in several metabolites, including excitotoxic neurotransmitters. Our study highlights the potential therapeutic significance of targeting FABP7 in NIHL.

DOI: https://doi.org/10.1038/s41598-023-48702-4
Biochem Biophys Res Commun. 2023 Nov 20. pii: S0006-291X(23)01347-5. [Epub ahead of print]691 149253

An ex vivo screening using mouse brain mitochondria identified seco-cycline D as an inhibitor of mitochondrial permeability transition pore.

Mie Kubota-Sakashita, Hirochika Kawakami, Ko Kikuzato, Fumiyuki Shirai, Takemichi Nakamura, Tadafumi Kato.

  Mitochondrial dysfunction is implicated in neuropsychiatric disorders. Inhibition of mitochondrial permeability transition pore (mPTP) and thereby enhancement of mitochondrial Ca2+ retention capacity (CRC) is a promising treatment strategy. Here, we screened 1718 compounds to search for drug candidates inhibiting mPTP by measuring their effects on CRC in mitochondria isolated from mouse brains. We identified seco-cycline D (SCD) as an active compound. SCD and its derivative were more potent than a known mPTP inhibitor, cyclosporine A (CsA). The mechanism of action of SCD was suggested likely to be different from CsA that acts on cyclophilin D. Repeated administration of SCD decreased ischemic area in a middle cerebral artery occlusion model in mice. These results suggest that SCD is a useful probe to explore mPTP function.

Keywords:  Calcium; Mitochondria; Mitochondrial permeability transition pore; Neuropsychiatric disorders; Seco-cycline D

DOI:  https://doi.org/10.1016/j.bbrc.2023.149253
Cell Rep. 2023 Nov 30. pii: S2211-1247(23)01526-7. [Epub ahead of print]42(12): 113514

Astrocytes produce nitric oxide via nitrite reduction in mitochondria to regulate cerebral blood flow during brain hypoxia.

Isabel N Christie, Shefeeq M Theparambil, Alice Braga, Maxim Doronin, Patrick S Hosford, Alexey Brazhe, Alexander Mascarenhas, Shereen Nizari, Anna Hadjihambi, Jack A Wells, Adrian Hobbs, Alexey Semyanov, Andrey Y Abramov, Plamena R Angelova, Alexander V Gourine.

  During hypoxia, increases in cerebral blood flow maintain brain oxygen delivery. Here, we describe a mechanism of brain oxygen sensing that mediates the dilation of intraparenchymal cerebral blood vessels in response to reductions in oxygen supply. In vitro and in vivo experiments conducted in rodent models show that during hypoxia, cortical astrocytes produce the potent vasodilator nitric oxide (NO) via nitrite reduction in mitochondria. Inhibition of mitochondrial respiration mimics, but also occludes, the effect of hypoxia on NO production in astrocytes. Astrocytes display high expression of the molybdenum-cofactor-containing mitochondrial enzyme sulfite oxidase, which can catalyze nitrite reduction in hypoxia. Replacement of molybdenum with tungsten or knockdown of sulfite oxidase expression in astrocytes blocks hypoxia-induced NO production by these glial cells and reduces the cerebrovascular response to hypoxia. These data identify astrocyte mitochondria as brain oxygen sensors that regulate cerebral blood flow during hypoxia via release of nitric oxide.

Keywords:  CP: Metabolism; CP: Neuroscience; astrocytes; brain; cerebral blood flow; free radical; hypoxia; mitochondria; nitric oxide; nitrite; oxygen; sulfite oxidase

DOI:  https://doi.org/10.1016/j.celrep.2023.113514
Adv Biol Regul. 2023 Nov 30. pii: S2212-4926(23)00047-7. [Epub ahead of print] 101001

A new role for phosphoinositides in regulating mitochondrial dynamics.

Sonia Raveena Lourdes, Rajendra Gurung, Saveen Giri, Christina A Mitchell, Meagan J McGrath.

  Phosphoinositides are a minor group of membrane-associated phospholipids that are transiently generated on the cytoplasmic leaflet of many organelle membranes and the plasma membrane. There are seven functionally distinct phosphoinositides, each derived via the reversible phosphorylation of phosphatidylinositol in various combinations on the inositol ring. Their generation and termination is tightly regulated by phosphatidylinositol-kinases and -phosphatases. These enzymes can function together in an integrated and coordinated manner, whereby the phosphoinositide product of one enzyme may subsequently serve as a substrate for another to generate a different phosphoinositide species. This regulatory mechanism not only enables the transient generation of phosphoinositides on membranes, but also more complex sequential or bidirectional conversion pathways, and phosphoinositides can also be transferred between organelles via membrane contacts. It is this capacity to fine-tune phosphoinositide signals that makes them ideal regulators of membrane organization and dynamics, through their recruitment of signalling, membrane altering and lipid transfer proteins. Research spanning several decades has provided extensive evidence that phosphoinositides are major gatekeepers of membrane organization, with roles in endocytosis, exocytosis, autophagy, lysosome dynamics, vesicular transport and secretion, cilia, inter-organelle membrane contact, endosome maturation and nuclear function. By contrast, there has been remarkably little known about the role of phosphoinositides at mitochondria - an enigmatic and major knowledge gap, with challenges in reliably detecting phosphoinositides at this site. Here we review recent significant breakthroughs in understanding the role of phosphoinositides in regulating mitochondrial dynamics and metabolic function.

Keywords:  Mitochondria; Mitochondrial fission; PI(4,5)P(2); PI3P; PI4P; Phosphoinositide

DOI:  https://doi.org/10.1016/j.jbior.2023.101001
Mol Genet Metab Rep. 2023 Dec;37 101004

An unusually mild case of biotin-thiamine-responsive basal ganglia disease.

Gurnoor Lail, Susan Blaser, Michal Inbar-Feigenberg.

  Background: Biotin-Thiamine-Responsive Basal Ganglia Disease (BTBGD) is a treatable neurometabolic condition associated with pathogenic variants in the SLC19A3 gene. The classical childhood-onset phenotype presents at a mean age of 4 years, ranging from birth to 12 years. These patients present with subacute encephalopathy, dysarthria, dysphagia, dystonia, external ophthalmoplegia, seizures, quadriparesis, and even death. Chronically, an MRI brain reveals atrophy and necrosis of the basal ganglia.Case report: A 16-year-old girl presented in the context of pneumonia with gradual-onset, slowly progressive neurological symptoms. These initial symptoms self-resolved, without treatment with biotin or thiamine, though she had persistent concerns with her writing and memory. MRI brain noted bilateral abnormal signals in the basal ganglia, involving the head and body of the caudate nuclei and the putamen. Whole-exome sequencing (WES) revealed homozygosity for a likely pathogenic variant in the SLC19A3 gene, c.517A > G (p.N173D). Her residual neurological symptoms resolved with biotin and thiamine treatment, with the exception of ongoing memory concerns.
Conclusion: We describe a patient presenting with an atypical form of the classical childhood-onset phenotype of BTBGD. Our case emphasizes that BTBGD is a condition that should be considered as a potential diagnosis in all children, including older children, presenting with the new onset of even minor neurological deficits in the context of illness. It highlights the importance of brain MRI and WES in identifying patients with atypical presentations.

Keywords:  Biotin-Thiamine-Responsive Basal Ganglia Disease (BTBGD); Inborn errors of metabolism (IEM); Leukoencephalopathy; Neurogenetic; Neurometabolic

DOI:  https://doi.org/10.1016/j.ymgmr.2023.101004
bioRxiv. 2023 Nov 21. pii: 2023.11.21.568116. [Epub ahead of print]

Temporal gene expression changes and affected pathways in neurodevelopment of a mouse model of Smith-Lemli-Opitz syndrome.

Amy Li, Hideaki Tomita, Libin Xu.

Smith-Lemli-Opitz syndrome is an autosomal recessive disorder that arises from mutations in the gene DHCR7 , which encodes the terminal enzyme of cholesterol biosynthesis, leading to decreased production of cholesterol and accumulation of the cholesterol precursor, 7-dehydrocholesterol, and its oxysterol metabolites. The disorder displays a wide range of neurodevelopmental defects, intellectual disability, and behavioral problems. However, an in-depth study on the temporal changes of gene expression in the developing brains of SLOS mice has not been done before. In this work, we carried out the transcriptomic analysis of whole brains from WT and Dhcr7 -KO mice at four-time points through postnatal day 0. First, we observed the expected downregulation of the Dhcr7 gene in the Dhcr7 -KO mouse model, as well as gene expression changes of several other genes involved in cholesterol biosynthesis throughout all time points. Pathway and GO term enrichment analyses revealed affected signaling pathways and biological processes that were shared amongst time points and unique to individual time points. Specifically, the pathways important for embryonic development, including Hippo, Wnt, and TGF-β signaling pathways are the most significantly affected at the earliest time point, E12.5. Additionally, neurogenesis-related GO terms were enriched in earlier time points, consistent with the timing of development. Conversely, pathways related to synaptogenesis, which occurs later in development compared to neurogenesis, are significantly affected at the later time points, E16.5 and PND0, including the cholinergic, glutamatergic, and GABAergic synapses. The impact of these transcriptomic changes and enriched pathways is discussed in the context of known biological phenotypes of SLOS.

DOI: https://doi.org/10.1101/2023.11.21.568116
Neuropsychopharmacol Rep. 2023 Dec 06.

Quantification of cytosine modifications in the aged mouse brain.

Hiroko Sugawara, Akitoshi Date, Satoshi Fuke, Yutaka Nakachi, Tadafumi Kato, Minoru Narita, Miki Bundo, Kazuya Iwamoto.

  Quantifying cytosine modifications in various brain regions provides important insights into the gene expression regulation and pathophysiology of neuropsychiatric disorders. In this study, we quantified 5-methylcytosine (5-mC), 5-hydroxymethylation (5-hmC), and 5-formylcytosine (5-fC) levels in five brain regions (the frontal lobe, cerebral cortical region without frontal lobe, hippocampus, basal ganglia, and the cerebellum) and the heart at three developmental periods (12, 48, and 101 weeks). We observed significant regional variations in cytosine modification. Notably, regional variations were generally maintained throughout development, suggesting that epigenetic regulation is unique to each brain region and remains relatively stable with age. The 5-mC and 5-hmC levels were positively correlated, although the extent of the correlations seemed to differ in different brain regions. On the contrary, 5-fC levels did not correlate with 5-mC or 5-hmC levels. Additionally, we observed an age-dependent decrease in 5-fC levels in the basal ganglia, suggesting a unique epigenetic regulation mechanism. Further high-resolution studies using animal models of neuropsychiatric disorders as well as postmortem brain evaluation are warranted.

Keywords:  5-formylcytosine: 5-fC; 5-hydroxymethycytosine: 5-hmC; 5-methylcytosine: 5-mC; aging; basal ganglia

DOI:  https://doi.org/10.1002/npr2.12396
Nat Commun. 2023 Dec 05. 14(1): 8039

A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence.

Ming Jiang, Mirjam C W Huizenga, Jonah L Wirt, Janos Paloczi, Avand Amedi, Richard J B H N van den Berg, Joerg Benz, Ludovic Collin, Hui Deng, Xinyu Di, Wouter F Driever, Bogdan I Florea, Uwe Grether, Antonius P A Janssen, Thomas Hankemeier, Laura H Heitman, Tsang-Wai Lam, Florian Mohr, Anto Pavlovic, Iris Ruf, Helma van den Hurk, Anna F Stevens, Daan van der Vliet, Tom van der Wel, Matthias B Wittwer, Constant A A van Boeckel, Pal Pacher, Andrea G Hohmann, Mario van der Stelt.

Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl4-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB1 activation. Antinociceptive efficacy of LEI-515 was blocked by CB2, but not CB1, antagonists. The CB1 antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.

DOI: https://doi.org/10.1038/s41467-023-43606-3