Publications by authors named "Daniel C Anthony"

122 Publications

Selective blood-brain barrier permeabilisation of brain metastases by a type-1 receptor selective tumour necrosis factor mutein.

Neuro Oncol 2021 Jul 23. Epub 2021 Jul 23.

Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.

Background: Metastasis to the brain is a major challenge with poor prognosis. The blood-brain barrier (BBB) is a significant impediment to effective treatment, being intact during the early stages of tumour development and heterogeneously permeable at later stages. Intravenous injection of tumour necrosis factor (TNF) selectively induces BBB permeabilisation at sites of brain micrometastasis, in a TNF type-1 receptor (TNFR1) dependent manner. Here, to enable clinical translation, we have developed a TNFR1-selective agonist variant of human TNF that induces BBB permeabilisation, whilst minimising potential toxicity.

Methods: A library of human TNF muteins (mutTNF) were generated and assessed for binding specificity to mouse and human TNFR1/2, endothelial permeabilising activity in vitro, potential immunogenicity and circulatory half-life. The permeabilising ability of the most promising variant was assessed in vivo in a model of brain metastasis.

Results: The primary mutTNF variant showed similar affinity for human TNFR1 than wild-type human TNF, similar affinity for mouse TNFR1 as wild-type mouse TNF, undetectable binding to human/mouse TNFR2, low potential immunogenicity and permeabilisation of an endothelial monolayer. Circulatory half-life was similar to mouse/human TNF and BBB permeabilisation was induced selectively at sites of micrometastases in vivo, with a time window of ≥24h and enabling delivery of agents within a therapeutically-relevant range (0.5-150kDa), including the clinically approved therapy, trastuzumab.

Conclusions: We have developed a clinically-translatable mutTNF that selectively opens the BBB at micrometastatic sites, whilst leaving the rest of the cerebrovasculature intact. This approach will open a window for brain metastasis treatment that currently does not exist.
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http://dx.doi.org/10.1093/neuonc/noab177DOI Listing
July 2021

Integrative biochemical, proteomics and metabolomics cerebrospinal fluid biomarkers predict clinical conversion to multiple sclerosis.

Brain Commun 2021 19;3(2):fcab084. Epub 2021 Apr 19.

Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.

Eighty-five percent of multiple sclerosis cases begin with a discrete attack termed clinically isolated syndrome, but 37% of clinically isolated syndrome patients do not experience a relapse within 20 years of onset. Thus, the identification of biomarkers able to differentiate between individuals who are most likely to have a second clinical attack from those who remain in the clinically isolated syndrome stage is essential to apply a personalized medicine approach. We sought to identify biomarkers from biochemical, metabolic and proteomic screens that predict clinically defined conversion from clinically isolated syndrome to multiple sclerosis and generate a multi-omics-based algorithm with higher prognostic accuracy than any currently available test. An integrative multi-variate approach was applied to the analysis of cerebrospinal fluid samples taken from 54 individuals at the point of clinically isolated syndrome with 2-10 years of subsequent follow-up enabling stratification into clinical converters and non-converters. Leukocyte counts were significantly elevated at onset in the clinical converters and predict the occurrence of a second attack with 70% accuracy. Myo-inositol levels were significantly increased in clinical converters while glucose levels were decreased, predicting transition to multiple sclerosis with accuracies of 72% and 63%, respectively. Proteomics analysis identified 89 novel gene products related to conversion. The identified biochemical and protein biomarkers were combined to produce an algorithm with predictive accuracy of 83% for the transition to clinically defined multiple sclerosis, outperforming any individual biomarker in isolation including oligoclonal bands. The identified protein biomarkers are consistent with an exaggerated immune response, perturbed energy metabolism and multiple sclerosis pathology in the clinical converter group. The new biomarkers presented provide novel insight into the molecular pathways promoting disease while the multi-omics algorithm provides a means to more accurately predict whether an individual is likely to convert to clinically defined multiple sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcab084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111065PMC
April 2021

Non-neuronal cells in amyotrophic lateral sclerosis - from pathogenesis to biomarkers.

Nat Rev Neurol 2021 Jun 29;17(6):333-348. Epub 2021 Apr 29.

Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.

The prevailing motor neuron-centric view of amyotrophic lateral sclerosis (ALS) pathogenesis could be an important factor in the failure to identify disease-modifying therapy for this neurodegenerative disorder. Non-neuronal cells have crucial homeostatic functions within the CNS and evidence of involvement of these cells in the pathophysiology of several neurodegenerative disorders, including ALS, is accumulating. Microglia and astrocytes, in crosstalk with peripheral immune cells, can exert both neuroprotective and adverse effects, resulting in a highly nuanced range of neuronal and non-neuronal cell interactions. This Review provides an overview of the diverse roles of non-neuronal cells in relation to the pathogenesis of ALS and the emerging potential of non-neuronal cell biomarkers to advance therapeutic development.
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http://dx.doi.org/10.1038/s41582-021-00487-8DOI Listing
June 2021

Anti-CD20 Disrupts Meningeal B-Cell Aggregates in a Model of Secondary Progressive Multiple Sclerosis.

Neurol Neuroimmunol Neuroinflamm 2021 05 2;8(3). Epub 2021 Mar 2.

From the Department of Pharmacology (J.R., Y.Z.), University of Oxford; University of Basel (D.L.), Switzerland; Deutsches Rheumaforschungszentrum (DRFZ) and Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin (J.R., A.E.H.), Germany; Roche Innovation Center (E.U.), Basel, Switzerland; and Department of Pharmacology (D.C.A.), University of Oxford, UK.

Objective: Therapies targeting B cells have been used in the clinic for multiple sclerosis (MS). In patients with relapsing MS, anti-CD20 therapy often suppresses relapse activity; yet, their effect on disease progression has been disappointing. Most anti-CD20 therapeutic antibodies are type I, but within the unique microenvironment of the brain, type II antibodies may be more beneficial, as type II antibodies exhibit reduced complement-dependent cytotoxicity and they have an increased capacity to induce direct cell death that is independent of the host immune response.

Methods: We compared the effect of type I with type II anti-CD20 therapy in a new rodent model of secondary progressive MS (SPMS), which recapitulates the principal histopathologic features of MS including meningeal B-cell aggregates. Focal MS-like lesions were induced by injecting heat-killed into the piriform cortex of MOG-immunized mice. Groups of mice were treated with anti-CD20 antibodies (type I [rituxumab, 10 mg/kg] or type II [GA101, 10 mg/kg]) 4 weeks after lesion initiation, and outcomes were evaluated by immunohistochemistry.

Results: Anti-CD20 therapy decreased the extent of glial activation, significantly decreased the number of B and T lymphocytes in the lesion, and resulted in disruption of the meningeal aggregates. Moreover, at the given dose, the type II anti-CD20 therapy was more efficacious than the type I and also protected against neuronal death.

Conclusions: These results indicate that anti-CD20 may be an effective therapy for SPMS with B-cell aggregates and that the elimination of CD20 B cells alone is sufficient to cause disruption of aggregates in the brain.
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http://dx.doi.org/10.1212/NXI.0000000000000975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931641PMC
May 2021

Acute IL-1RA treatment suppresses the peripheral and central inflammatory response to spinal cord injury.

J Neuroinflammation 2021 Jan 6;18(1):15. Epub 2021 Jan 6.

Department of Pharmacology, The University of Oxford, Mansfield Road, Oxford, UK.

Background: The acute phase response (APR) to CNS insults contributes to the overall magnitude and nature of the systemic inflammatory response. Aspects of this response are thought to drive secondary inflammatory pathology at the lesion site, and suppression of the APR can therefore afford some neuroprotection. In this study, we examined the APR in a mouse model of traumatic spinal cord injury (SCI), along with its relationship to neutrophil recruitment during the immediate aftermath of the insult. We specifically investigated the effect of IL-1 receptor antagonist (IL-1RA) administration on the APR and leukocyte recruitment to the injured spinal cord.

Methods: Adult female C57BL/6 mice underwent either a 70kD contusive SCI, or sham surgery, and tissue was collected at 2, 6, 12, and 24 hours post-operation. For IL-1RA experiments, SCI mice received two intraperitoneal injections of human IL-1RA (100mg/kg), or saline as control, immediately following, and 5 hours after impact, and animals were sacrificed 6 hours later. Blood, spleen, liver and spinal cord were collected to study markers of central and peripheral inflammation by flow cytometry, immunohistochemistry and qPCR. Results were analysed by two-way ANOVA or student's t-test, as appropriate.

Results: SCI induced a robust APR, hallmarked by elevated hepatic expression of pro-inflammatory marker genes and a significantly increased neutrophil presence in the blood, liver and spleen of these animals, as early as 2 hours after injury. This peripheral response preceded significant neutrophil infiltration of the spinal cord, which peaked 24 hours post-SCI. Although expression of IL-1RA was also induced in the liver following SCI, its response was delayed compared to IL-1β. Exogenous administration of IL-1RA during this putative therapeutic window was able to suppress the hepatic APR, as evidenced by a reduction in CXCL1 and SAA-2 expression as well as a significant decrease in neutrophil infiltration in both the liver and the injured spinal cord itself.

Conclusions: Our data indicate that peripheral administration of IL-1RA can attenuate the APR which in turn reduces immune cell infiltration at the spinal cord lesion site. We propose IL-1RA treatment as a viable therapeutic strategy to minimise the harmful effects of SCI-induced inflammation.
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http://dx.doi.org/10.1186/s12974-020-02050-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788822PMC
January 2021

Altered behaviour, dopamine and norepinephrine regulation in stressed mice heterozygous in TPH2 gene.

Prog Neuropsychopharmacol Biol Psychiatry 2021 06 28;108:110155. Epub 2020 Oct 28.

Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Department of Pharmacology, Oxford University, Oxford, United Kingdom. Electronic address:

Gene-environment interaction (GxE) determines the vulnerability of an individual to a spectrum of stress-related neuropsychiatric disorders. Increased impulsivity, excessive aggression, and other behavioural characteristics are associated with variants within the tryptophan hydroxylase-2 (Tph2) gene, a key enzyme in brain serotonin synthesis. This phenotype is recapitulated in naïve mice with complete, but not with partial Tph2 inactivation. Tph2 haploinsufficiency in animals reflects allelic variation of Tph2 facilitating the elucidation of respective GxE mechanisms. Recently, we showed excessive aggression and altered serotonin brain metabolism in heterozygous Tph2-deficient male mice (Tph2) after predator stress exposure. Here, we sought to extend these studies by investigating aggressive and anxiety-like behaviours, sociability, and the brain metabolism of dopamine and noradrenaline. Separately, Tph2 mice were examined for exploration activity in a novel environment and for the potentiation of helplessness in the modified swim test (ModFST). Predation stress procedure increased measures of aggression, dominancy, and suppressed sociability in Tph2 mice, which was the opposite of that observed in control mice. Anxiety-like behaviour was unaltered in the mutants and elevated in controls. Tph2 mice exposed to environmental novelty or to the ModFST exhibited increased novelty exploration and no increase in floating behaviour compared to controls, which is suggestive of resilience to stress and despair. High-performance liquid chromatography (HPLC) revealed significant genotype-dependent differences in the metabolism of dopamine, and norepinephrine within the brain tissue. In conclusion, environmentally challenged Tph2 mice exhibit behaviours that resemble the behaviour of non-stressed null mutants, which reveals how GxE interaction studies can unmask latent genetically determined predispositions.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110155DOI Listing
June 2021

Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites.

Sci Rep 2020 10 8;10(1):16857. Epub 2020 Oct 8.

Department of Psychiatry, Warneford Hospital, University of Oxford, Warneford Lane, Oxford, OX3 7JX, UK.

Post-inflammatory behaviours in rodents are widely used to model human depression and to test the efficacy of novel anti-depressants. Mice injected with lipopolysaccharide (LPS) display a depressive-like phenotype twenty-four hours after endotoxin administration. Despite the widespread use of this model, the mechanisms that underlie the persistent behavioural changes after the transient peripheral inflammatory response remain elusive. The study of the metabolome, the collection of all the small molecule metabolites in a sample, combined with multivariate statistical techniques provides a way of studying biochemical pathways influenced by an LPS challenge. Adult male CD-1 mice received an intraperitoneal injection of either LPS (0.83 mg/kg) or saline, and were assessed for depressive-like behaviour 24 h later. In a separate mouse cohort, pro-inflammatory cytokine gene expression and 1H nuclear magnetic resonance (NMR) metabolomics measurements were made in brain tissue and blood. Statistical analyses included Independent Sample t-tests for gene expression data, and supervised multi-variate analysis using orthogonal partial least squares discriminant analysis for metabolomics. Both plasma and brain metabolites in male mice were altered following a single peripheral LPS challenge that led to depressive-like behaviour in the forced swim test. The plasma metabolites altered by LPS are involved in energy metabolism, including lipoproteins, glucose, creatine, and isoleucine. In the brain, glutamate, serine, and N-acetylaspartate (NAA) were reduced after LPS, whereas glutamine was increased. Serine-modulated glutamatergic signalling and changes in bioenergetics may mediate the behavioural phenotype induced by LPS. In light of other data supporting a central imbalance of glutamate-glutamine cycling in depression, our results suggest that aberrant central glutaminergic signalling may underpin the depressive-like behaviours that result from both inflammation and non-immune pathophysiology. Normalising glutaminergic signalling, rather than seeking to increase serotonergic signalling, might prove to be a more coherent approach to the development of new treatments for mood disorder.
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http://dx.doi.org/10.1038/s41598-020-74008-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545201PMC
October 2020

Mom's diet matters: Maternal prebiotic intake in mice reduces anxiety and alters brain gene expression and the fecal microbiome in offspring.

Brain Behav Immun 2021 01 5;91:230-244. Epub 2020 Oct 5.

Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford OX3 7JX, UK. Electronic address:

Compelling evidence links enteric microbes to brain function and behavior. Galacto-oligosaccharide prebiotics have been shown to modulate the composition of gut flora and induce metabolic, neurochemical, and behavioral changes in adult rodents. Despite the brain being most susceptible to environmental factors, such as nutrients and toxins, during the earliest stages of development, it is unknown whether maternal prebiotic supplementation during gestation and lactation influences the offspring gut microbiome, brain, or behavior. The aim of this study was to test whether maternal galacto-oligosaccharide intake during pregnancy and lactation alters the brain and behavior in naïve and endotoxin-challenged offspring. CD1 female mice received either normal drinking water or water supplemented with Bimuno® galacto-oligosaccharides (B-GOS) during gestation and suckling. Offspring behavior was tested at weaning age or adulthood, and a cross-foster design was employed in a separate cohort to differentiate between effects of prenatal and postnatal maternal B-GOS intake. Lipopolysaccharide was also administered to pups at postnatal day 9 to determine whether maternal B-GOS influences the neurobiological and behavioral effects of a neonatal pro-inflammatory challenge in adulthood. Fecal microbiome composition and metabolites were analyzed to explore potential relationships between the maternal microbiome, the offspring gut microbiome, and the offspring brain and behavior. Maternal B-GOS supplementation increased exploratory behavior and reduced expression of hippocampal glutamate receptor genes in young, weaning-age offspring. In addition, postnatal, but not prenatal, B-GOS supplementation increased fecal butyrate and propionate levels. Finally, in adult offspring, perinatal B-GOS intake increased cortical glutamate receptor subunits in females, increased social preference, and reduced anxiety. We provide novel and comprehensive evidence for the influence of maternal prebiotic intake on offspring behavior, brain gene expression, and gut microbiome composition in mice.
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http://dx.doi.org/10.1016/j.bbi.2020.09.034DOI Listing
January 2021

Dibenzoylthiamine Has Powerful Antioxidant and Anti-Inflammatory Properties in Cultured Cells and in Mouse Models of Stress and Neurodegeneration.

Biomedicines 2020 Sep 18;8(9). Epub 2020 Sep 18.

Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium.

Thiamine precursors, the most studied being benfotiamine (BFT), have protective effects in mouse models of neurodegenerative diseases. BFT decreased oxidative stress and inflammation, two major characteristics of neurodegenerative diseases, in a neuroblastoma cell line (Neuro2a) and an immortalized brain microglial cell line (BV2). Here, we tested the potential antioxidant and anti-inflammatory effects of the hitherto unexplored derivative O,S-dibenzoylthiamine (DBT) in these two cell lines. We show that DBT protects Neuro2a cells against paraquat (PQ) toxicity by counteracting oxidative stress at low concentrations and increases the synthesis of reduced glutathione and NADPH in a Nrf2-independent manner. In BV2 cells activated by lipopolysaccharides (LPS), DBT significantly decreased inflammation by suppressing translocation of NF-κB to the nucleus. Our results also demonstrate the superiority of DBT over thiamine and other thiamine precursors, including BFT, in all of the in vitro models. Finally, we show that the chronic administration of DBT arrested motor dysfunction in FUS transgenic mice, a model of amyotrophic lateral sclerosis, and it reduced depressive-like behavior in a mouse model of ultrasound-induced stress in which it normalized oxidative stress marker levels in the brain. Together, our data suggest that DBT may have therapeutic potential for brain pathology associated with oxidative stress and inflammation by novel, coenzyme-independent mechanisms.
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http://dx.doi.org/10.3390/biomedicines8090361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555733PMC
September 2020

Astroglia-specific contributions to the regulation of synapses, cognition and behaviour.

Neurosci Biobehav Rev 2020 11 6;118:331-357. Epub 2020 Aug 6.

Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, 66075-110, Belém, Brazil. Electronic address:

Astrocytes are a heterogeneous population of neural cells with diverse structural, functional and molecular characteristics responsible for homeostasis and protection of the central nervous system (CNS). Unlike neurones, astrocytes do not generate action potentials, but employ fluctuations of cytosolic ions as a substrate for their excitability. Ionic signals are associated with neuronal activity and these signals initiate an array of responses ranging from the activation of plasmalemmal homeostatic transporters to the secretion of numerous signalling molecules including neuromodulators, neurotransmitter precursors, metabolic substrates, trophic factors and cytokines. Thus, astrocytes regulate the synaptic connectivity of the neuronal networks by supporting neurotransmitter metabolism, synaptogenesis, synaptic elimination and the synaptic plasticity that contributes to cognitive processing including learning, memory, emotionality and behaviour. Astroglia-specific regulatory pathways affect the most fundamental properties of neuronal networks from their excitability to synaptic connectivity. Thus, it is the concerted action of glia and neurones, which, through distinct mechanisms, produce the behavioural outputs of the ultimate control centre that we call the brain.
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http://dx.doi.org/10.1016/j.neubiorev.2020.07.039DOI Listing
November 2020

A blood-based metabolomics test to distinguish relapsing-remitting and secondary progressive multiple sclerosis: addressing practical considerations for clinical application.

Sci Rep 2020 07 24;10(1):12381. Epub 2020 Jul 24.

Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.

The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) represents a huge clinical challenge. We previously demonstrated that serum metabolomics could distinguish RRMS from SPMS with high diagnostic accuracy. As differing sample-handling protocols can affect the blood metabolite profile, it is vital to understand which factors may influence the accuracy of this metabolomics-based test in a clinical setting. Herein, we aim to further validate the high accuracy of this metabolomics test and to determine if this is maintained in a 'real-life' clinical environment. Blood from 31 RRMS and 28 SPMS patients was subjected to different sample-handling protocols representing variations encountered in clinics. The effect of freeze-thaw cycles (0 or 1) and time to erythrocyte removal (30, 120, or 240 min) on the accuracy of the test was investigated. For test development, samples from the optimised protocol (30 min standing time, 0 freeze-thaw) were used, resulting in high diagnostic accuracy (mean ± SD, 91.0 ± 3.0%). This test remained able to discriminate RRMS and SPMS samples that had experienced additional freeze-thaw, and increased standing times of 120 and 240 min with accuracies ranging from 85.5 to 88.0%, because the top discriminatory metabolite biomarkers from the optimised protocol remained discriminatory between RRMS and SPMS despite these sample-handling variations. In conclusion, while strict sample-handling is essential for the development of metabolomics-based blood tests, the results confirmed that the RRMS vs. SPMS test is resistant to sample-handling variations and can distinguish these two MS stages in the clinics.
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http://dx.doi.org/10.1038/s41598-020-69119-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381627PMC
July 2020

Stress-induced aggression in heterozygous TPH2 mutant mice is associated with alterations in serotonin turnover and expression of 5-HT6 and AMPA subunit 2A receptors.

J Affect Disord 2020 07 1;272:440-451. Epub 2020 May 1.

Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany; Institute of General Pathology and Pathophysiology, Moscow, Russia. Electronic address:

Background: The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2-/-) are naturally highly aggressive, while heterozygous mice (Tph2+/-) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically 'susceptible' heterozygous mice (Tph2+/-).

Methods: Tph2+/- male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied.

Results: Stressed Tph2+/- mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/- mice.

Limitations: Rescue experiments would help to verify causal relationships of reported changes.

Conclusions: The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes.
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http://dx.doi.org/10.1016/j.jad.2020.04.014DOI Listing
July 2020

A single administration of the antibiotic, minocycline, reduces fear processing and improves implicit learning in healthy volunteers: analysis of the serum metabolome.

Transl Psychiatry 2020 05 13;10(1):148. Epub 2020 May 13.

Department of Psychiatry, University of Oxford, Oxford, UK.

Minocycline has shown therapeutic promise in pre-clinical animal models and early phase clinical trials for a variety of psychiatric disorders. Previous studies on minocycline have shown its ability to suppress microglia activity and reduce inflammatory cytokine levels, and its amelioration of depressive-like behaviour in animals and humans. However, the underlying mechanisms that lead to minocycline's psychotropic effects are not clear. In this study, we investigated the psychological and biochemical effects of an acute dose of minocycline or placebo in 40 healthy adult volunteers. Psychological changes in emotional processing, implicit learning, and working memory were assessed. Plasma inflammatory markers, measured with enzyme-linked immunosorbent assays, and serum metabolites, measured with proton nuclear magnetic resonance combined with multi-variate analysis techniques, were also studied. Results showed that minocycline administration decreased fear misclassification and increased contextual learning, which suggested that reducing negative biases and improving cognition, respectively, may underlie the antidepressant actions of this agent. An examination of serum metabolites revealed higher levels of lipoproteins, particularly cholesterol, in the minocycline group. Minocycline also decreased circulating concentrations of the inflammatory marker C-Reactive Peptide, which is consistent with previous research. These effects highlight two important psychological mechanisms that may be relevant to the efficacy of minocycline reported in clinical trials, and also suggest a possible largely unexplored lipid-related biochemical pathway for the action of this drug.
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http://dx.doi.org/10.1038/s41398-020-0818-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220900PMC
May 2020

Enhanced conditioning of adverse memories in the mouse modified swim test is associated with neuroinflammatory changes - Effects that are susceptible to antidepressants.

Neurobiol Learn Mem 2020 07 20;172:107227. Epub 2020 Apr 20.

Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht University, Maastricht, Netherlands; Sechenov First Moscow State Medical University, Institute of Molecular Medicine Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Moscow, Russia. Electronic address:

Deficient learning and memory are well-established pathophysiologic features of depression, however, mechanisms of the enhanced learning of aversive experiences associated with this disorder are poorly understood. Currently, neurobiological mechanisms of enhanced retention of aversive memories during depression, and, in particular, their relation to neuroinflammation are unclear. As the association between major depressive disorder and inflammation has been recognized for some time, we aimed to address whether neuroinflammatory changes are involved in enhanced learning of adversity in a depressive state. To study this question, we used a recently described mouse model of enhanced contextual conditioning of aversive memories, the modified forced swim model (modFST). In this model, the classic two-day forced swim is followed by an additional delayed session on Day 5, where increased floating behaviour and upregulated glycogen synthase kinase-3 (GSK-3) are context-dependent. Here, increased time spent floating on Day 5, a parameter of enhanced learning of the adverse context, was accompanied by hypercorticosteronemia, increased gene expression of GSK-3α, GSK-3β, c-Fos, cyclooxygenase-1 (COX-1) and pro-inflammatory cytokines interleukin-1 beta (IL-1β), tumor necrosis factor (TNF), and elevated concentrations of protein carbonyl, a marker of oxidative stress, in the prefrontal cortex and hippocampus. There were significant correlations between cytokine levels and GSK-3β gene expression. Two-week administration of compounds with antidepressant properties, imipramine (7 mg/kg/day) or thiamine (vitamin B1; 200 mg/kg/day) ameliorated most of the modFST-induced changes. Thus, enhanced learning of adverse memories is associated with pro-inflammatory changes that should be considered for optimizing pharmacotherapy of depression associated with enhanced learning of aversive memories.
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http://dx.doi.org/10.1016/j.nlm.2020.107227DOI Listing
July 2020

Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner.

Cell 2020 03;180(5):833-846.e16

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia. Electronic address:

Cognitive dysfunction and reactive microglia are hallmarks of traumatic brain injury (TBI), yet whether these cells contribute to cognitive deficits and secondary inflammatory pathology remains poorly understood. Here, we show that removal of microglia from the mouse brain has little effect on the outcome of TBI, but inducing the turnover of these cells through either pharmacologic or genetic approaches can yield a neuroprotective microglial phenotype that profoundly aids recovery. The beneficial effects of these repopulating microglia are critically dependent on interleukin-6 (IL-6) trans-signaling via the soluble IL-6 receptor (IL-6R) and robustly support adult neurogenesis, specifically by augmenting the survival of newborn neurons that directly support cognitive function. We conclude that microglia in the mammalian brain can be manipulated to adopt a neuroprotective and pro-regenerative phenotype that can aid repair and alleviate the cognitive deficits arising from brain injury.
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http://dx.doi.org/10.1016/j.cell.2020.02.013DOI Listing
March 2020

Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity?

Front Neurosci 2020 18;14:24. Epub 2020 Feb 18.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands.

Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a "Western diet" (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different genotypes: homozygous () gene knockout ( : KO), heterozygous ( : HET), or wild-type mice ( : WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 () and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors and , as well as increased and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a (). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a "rescued" phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism.
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http://dx.doi.org/10.3389/fnins.2020.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041415PMC
February 2020

Metabolomics in multiple sclerosis disease course and progression.

Mult Scler 2020 04 22;26(5):591-598. Epub 2020 Jan 22.

Department of Pharmacology, University of Oxford, Oxford, UK.

Multiple sclerosis (MS) is associated with changes in the metabolome. Numerous studies employing varying metabolomics platforms have examined a range of biological material ranging from brain tissue to urine and demonstrated consistently alterations in multiple metabolic pathways in MS. We review not only the studies that describe the ability of metabolomics to differentiate MS patients from healthy controls and other neurological disease but also discuss the potential of metabolomics-based methods to build predictive models that are able to stage disease, monitor progression, and select the most appropriate therapy. The increasing number of impressive claims for the capacity of metabolomics to distinguish between different types of demyelinating disease suggests that the provision of such tests may be close at hand. Besides the ability to provide potential diagnostic and prognostic biomarkers, metabolomics also provides us with unique insights into the pathophysiology of the disease and helps identify metabolic pathways that may be potential therapeutic targets. Future studies will integrate metabolomics data with other omics techniques to provide further insight into the source of these metabolic abnormalities and help with identification of the most promising targets for therapeutic intervention.
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http://dx.doi.org/10.1177/1352458519876020DOI Listing
April 2020

Prefrontal cortex inflammation and liver pathologies accompany cognitive and motor deficits following Western diet consumption in non-obese female mice.

Life Sci 2020 Jan 13;241:117163. Epub 2019 Dec 13.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229ER Maastricht, the Netherlands; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Trubetskaya Str. 8, 119991 Moscow, Russia; Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080 Würzburg, Germany. Electronic address:

Aims: The high sugar and lipid content of the Western diet (WD) is associated with metabolic dysfunction, non-alcoholic steatohepatitis, and it is an established risk factor for neuropsychiatric disorders. Our previous studies reported negative effects of the WD on rodent emotionality, impulsivity, and sociability in adulthood. Here, we investigated the effect of the WD on motor coordination, novelty recognition, and affective behavior in mice as well as molecular and cellular endpoints in brain and peripheral tissues.

Main Methods: Female C57BL/6 J mice were fed the WD for three weeks and were investigated for glucose tolerance, insulin resistance, liver steatosis, and changes in motor coordination, object recognition, and despair behavior in the swim test. Lipids and liver injury markers, including aspartate-transaminase, alanine-transaminase and urea were measured in blood. Serotonin transporter (SERT) expression, the density of Iba1-positive cells and concentration of malondialdehyde were measured in brain.

Key Findings: WD-fed mice exhibited impaired glucose tolerance and insulin resistance, a loss of motor coordination, deficits in novel object exploration and recognition, increased helplessness, dyslipidemia, as well as signs of a non-alcoholic steatohepatitis (NASH)-like syndrome: liver steatosis and increased liver injury markers. Importantly, these changes were accompanied by decreased SERT expression, elevated numbers of microglia cells and malondialdehyde levels in, and restricted to, the prefrontal cortex.

Significance: The WD induces a spectrum of behaviors that are more reminiscent of ADHD and ASD than previously recognized and suggests that, in addition to the impairment of impulsivity and sociability, the consumption of a WD might be expected to exacerbate motor dysfunction that is also known to be associated with adult ADHD and ASD.
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http://dx.doi.org/10.1016/j.lfs.2019.117163DOI Listing
January 2020

Systemic Immune Response to Traumatic CNS Injuries-Are Extracellular Vesicles the Missing Link?

Front Immunol 2019 20;10:2723. Epub 2019 Nov 20.

Acute Stroke Programme, RDM-Investigative Medicine, University of Oxford, Oxford, United Kingdom.

Inflammation following traumatic injury to the central nervous system (CNS) persists long after the primary insult and is known to exacerbate cell death and worsen functional outcomes. Therapeutic interventions targeting this inflammation have been unsuccessful, which has been attributed to poor bioavailability owing to the presence of blood-CNS barrier. Recent studies have shown that the magnitude of the CNS inflammatory response is dependent on systemic inflammatory events. The acute phase response (APR) to CNS injury presents an alternative strategy to modulating the secondary phase of injury. However, the communication pathways between the CNS and the periphery remain poorly understood. Extracellular vesicles (EVs) are membrane bound nanoparticles that are regulators of intercellular communication. They are shed from cells of the CNS including microglia, astrocytes, neurons and endothelial cells, and are able to cross the blood-CNS barrier, thus providing an attractive candidate for initiating the APR after acute CNS injury. The purpose of this review is to summarize the current evidence that EVs play a critical role in the APR following CNS injuries.
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http://dx.doi.org/10.3389/fimmu.2019.02723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879545PMC
November 2020

Extracellular vesicle integrins act as a nexus for platelet adhesion in cerebral microvessels.

Sci Rep 2019 11 1;9(1):15847. Epub 2019 Nov 1.

Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, United Kingdom.

Circulating extracellular vesicles (EVs) regulate signaling pathways via receptor-ligand interactions and content delivery, after attachment or internalization by endothelial cells. However, they originate from diverse cell populations and are heterogeneous in composition. To determine the effects of specific surface molecules, the use of synthetic EV mimetics permits the study of specific EV receptor-ligand interactions. Here, we used endogenous EVs derived from the circulation of rats, as well as ligand-decorated synthetic microparticles (MPs) to examine the role of integrin αvβ3 in platelet adhesion under flow in structurally intact cerebral arteries. At an intraluminal pressure of 50 mmHg and flow rate of 10 µl/min, platelets were delivered to the artery lumen and imaged with whole-field fluorescent microscopy. Under basal conditions very few platelets bound to the endothelium. However, adhesion events were markedly increased following the introduction of arginine-glycine-aspartate (RGD)-labelled synthetic MPs or endogenously-derived EVs from experimental stroke animals carrying excess RGD proteins, including vitronectin, CD40-ligand and thrombospondin-1. These data, which were generated in a dynamic and physiologically relevant system, demonstrate the importance of vesicle-carried RGD ligands in platelet adherence to the cerebrovascular endothelium and highlight the ability of synthetic EVs to isolate and identify key components of the molecular handshake between EVs and their targets.
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http://dx.doi.org/10.1038/s41598-019-52127-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825169PMC
November 2019

Classifying the antibody-negative NMO syndromes: Clinical, imaging, and metabolomic modeling.

Neurol Neuroimmunol Neuroinflamm 2019 11 28;6(6):e626. Epub 2019 Oct 28.

From the Department of Pharmacology (T.Y, F.P., M.S., D.C.A.), University of Oxford, UK; Department of Neurology (T.Y.), National Neuroscience Institute, Singapore; Nuffield Department of Clinical Neurosciences (M.J., A.C., M.W., P.W., M.I.L., J.P.), John Radcliffe Hospital, University of Oxford, UK; Department of Chemistry, (T.D.W.C.), Chemistry Research Laboratory, University of Oxford, UK.

Objective: To determine whether unsupervised principal component analysis (PCA) of comprehensive clinico-radiologic data can identify phenotypic subgroups within antibody-negative patients with overlapping features of multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSDs), and to validate the phenotypic classifications using high-resolution nuclear magnetic resonance (NMR) plasma metabolomics with inference to underlying pathologies.

Methods: Forty-one antibody-negative patients were recruited from the Oxford NMO Service. Thirty-six clinico-radiologic parameters, focusing on features known to distinguish NMOSD and MS, were collected to build an unbiased PCA model identifying phenotypic subgroups within antibody-negative patients. Metabolomics data from patients with relapsing-remitting MS (RRMS) (n = 34) and antibody-positive NMOSD (Ab-NMOSD) (aquaporin-4 antibody n = 54, myelin oligodendrocyte glycoprotein antibody n = 20) were used to identify discriminatory plasma metabolites separating RRMS and Ab-NMOSD.

Results: PCA of the 36 clinico-radiologic parameters revealed 3 phenotypic subgroups within antibody-negative patients: an MS-like subgroup, an NMOSD-like subgroup, and a low brain lesion subgroup. Supervised multivariate analysis of metabolomics data from patients with RRMS and Ab-NMOSD identified myoinositol and formate as the most discriminatory metabolites (both higher in RRMS). Within antibody-negative patients, myoinositol and formate were significantly higher in the MS-like vs NMOSD-like subgroup; myoinositol (mean [SD], 0.0023 [0.0002] vs 0.0019 [0.0003] arbitrary units [AU]; = 0.041); formate (0.0027 [0.0006] vs 0.0019 [0.0006] AU; = 0.010) (AU).

Conclusions: PCA identifies 3 phenotypic subgroups within antibody-negative patients and that the metabolite discriminators of RRMS and Ab-NMOSD suggest that these groupings have some pathogenic meaning. Thus, the identified clinico-radiologic discriminators may provide useful diagnostic clues when seeing antibody-negative patients in the clinic.
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http://dx.doi.org/10.1212/NXI.0000000000000626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865851PMC
November 2019

What Do Microglia Really Do in Healthy Adult Brain?

Cells 2019 10 22;8(10). Epub 2019 Oct 22.

Laboratório de Farmacologia Molecular (Instituto de Ciências Biológicas), Universidade Federal do Pará, Belém 66075-110, Brasil.

Microglia originate from yolk sac-primitive macrophages and auto-proliferate into adulthood without replacement by bone marrow-derived circulating cells. In inflammation, stroke, aging, or infection, microglia have been shown to contribute to brain pathology in both deleterious and beneficial ways, which have been studied extensively. However, less is known about their role in the healthy adult brain. Astrocytes and oligodendrocytes are widely accepted to strongly contribute to the maintenance of brain homeostasis and to modulate neuronal function. On the other hand, contribution of microglia to cognition and behavior is only beginning to be understood. The ability to probe their function has become possible using microglial depletion assays and conditional mutants. Studies have shown that the absence of microglia results in cognitive and learning deficits in rodents during development, but this effect is less pronounced in adults. However, evidence suggests that microglia play a role in cognition and learning in adulthood and, at a cellular level, may modulate adult neurogenesis. This review presents the case for repositioning microglia as key contributors to the maintenance of homeostasis and cognitive processes in the healthy adult brain, in addition to their classical role as sentinels coordinating the neuroinflammatory response to tissue damage and disease.
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http://dx.doi.org/10.3390/cells8101293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829860PMC
October 2019

Effects of 50 Hz magnetic fields on circadian rhythm control in mice.

Bioelectromagnetics 2019 May 4;40(4):250-259. Epub 2019 Apr 4.

Public Health England, Chilton, United Kingdom.

Artificial light and power frequency magnetic fields are ubiquitous in the built environment. Light is a potent zeitgeber but it is unclear whether power frequency magnetic fields can influence circadian rhythm control. To study this possibility, 8-12-week-old male C57BL/6J mice were exposed for 30 min starting at zeitgeber time 14 (ZT14, 2 h into the dark period of the day) to 50 Hz magnetic fields at 580 μT using a pair of Helmholtz coils and/or a blue LED light at 700 lux or neither. Our experiments revealed an acute adrenal response to blue light, in terms of increased adrenal per1 gene expression, increased serum corticosterone levels, increased time spent sleeping, and decreased locomotor activity (in all cases, P < 0.0001) compared to an unexposed control group. There appeared to be no modulating effect of the magnetic fields on the response to light, and there was also no effect of the magnetic fields alone (in both cases, P > 0.05) except for a decrease in locomotor activity (P < 0.03). Gene expression of the cryptochromes cry1 and cry2 in the adrenals, liver, and hippocampus was also not affected by exposures (in all cases, P > 0.05). In conclusion, these results suggest that 50 Hz magnetic fields do not significantly affect the acute light response to a degree that can be detected in the adrenal response. Bioelectromagnetics. 2019;9999:XX-XX. © 2019 Bioelectromagnetics Society.
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http://dx.doi.org/10.1002/bem.22188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617993PMC
May 2019

Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice.

Neuropharmacology 2019 09 25;156:107543. Epub 2019 Feb 25.

Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL, 6229ER, Maastricht, Netherlands; Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University Trubetskaya Street 8-2, 119991, Moscow, Russia; Institute of General Pathology and Pathophysiology, Baltiiskaya Str, 8, 125315, Moscow, Russia. Electronic address:

The negative societal impacts associated with the increasing prevalence of violence and aggression is increasing, and, with this rise, is the need to understand the molecular and cellular changes that underpin ultrasound-induced aggressive behavior. In mice, stress-induced aggression is known to alter AMPA receptor subunit expression, plasticity markers, and oxidative stress within the brain. Here, we induced aggression in BALB/c mice using chronic ultrasound exposure and examined the impact of the psychoactive anti-oxidant compounds thiamine (vitamin B1), and its derivative benfotiamine, on AMPA receptor subunit expression, established plasticity markers, and oxidative stress. The administration of thiamine or benfotiamine (200 mg/kg/day) in drinking water decreased aggressive behavior following 3-weeks of ultrasound exposure and benfotiamine, reduced floating behavior in the swim test. The vehicle-treated ultrasound-exposed mice exhibited increases in protein carbonyl and total glutathione, altered AMPA receptor subunits expression, and decreased expression of plasticity markers. These ultrasound-induced effects were ameliorated by thiamine and benfotiamine treatment; in particular both antioxidants were able to reverse ultrasound-induced changes in GluA1 and GluA2 subunit expression, and, within the prefrontal cortex, significantly reversed the changes in protein carbonyl and polysialylated form of neural cell adhesion molecule (PSA-NCAM) expression levels. Benfotiamine was usually more efficacious than thiamine. Thus, the thiamine compounds were able to counteract ultrasound-induced aggression, which was accompanied by the normalization of markers that have been showed to be associated with ultrasound-induced aggression. These commonly used, orally-active compounds may have considerable potential for use in the control of aggression within the community. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.02.025DOI Listing
September 2019

Prebiotic reduction of brain histone deacetylase (HDAC) activity and olanzapine-mediated weight gain in rats, are acetate independent.

Neuropharmacology 2019 05 11;150:184-191. Epub 2019 Feb 11.

Department of Psychiatry, University of Oxford, Oxford, OX3 7JX, United Kingdom. Electronic address:

The intestinal microbiome is emerging as a novel therapeutic target owing to the wide range of potential health benefits that could result by manipulating the microbiota composition through relatively simple interventions. Ingestion of the prebiotic Bimuno™ galacto-oligosaccharide (B-GOS) is one such intervention that has been shown to attenuate olanzapine-induced weight gain and improve cognitive flexibility in rats, potentially through mechanisms involving acetate, the major short-chain fatty acid (SCFA) that is produced by B-GOS fermentation. The present study investigated the individual influences of B-GOS and sodium acetate intake on brain histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities, cortical and hippocampal expression of HDAC1-4 and N-methyl-d-aspartate receptor subunits in saline or olanzapine injected female rats. The effect of sodium acetate on olanzapine-induced weight gain was also investigated. Daily ingestion of B-GOS for 21 days, reduced HDAC activity and hippocampal HDAC-4, and elevated levels of cortical HDAC-1 and HDAC-3 mRNAs. Sodium acetate supplementation significantly decreased HAT, but not HDAC, activity and increased hippocampal HDAC-3 and HDAC-4 mRNAs. Olanzapine-induced weight gain and fourteen genera of intestinal bacteria, were not influenced by sodium acetate intake. Together these data suggests the effects of B-GOS in rats cannot be replicated by acetate ingestion, and that mechanisms beyond the production of this SCFA are likely to underlie the psychotropic and metabolic actions of this prebiotic.
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http://dx.doi.org/10.1016/j.neuropharm.2019.02.014DOI Listing
May 2019

Corrigendum: Early Growth Response Gene-2 Is Essential for M1 and M2 Macrophage Activation and Plasticity by Modulation of the Transcription Factor CEBPβ.

Front Immunol 2018 13;9:2923. Epub 2018 Dec 13.

Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.

[This corrects the article DOI: 10.3389/fimmu.2018.02515.].
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http://dx.doi.org/10.3389/fimmu.2018.02923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301196PMC
December 2018

Neuroinflammation and aberrant hippocampal plasticity in a mouse model of emotional stress evoked by exposure to ultrasound of alternating frequencies.

Prog Neuropsychopharmacol Biol Psychiatry 2019 03 22;90:104-116. Epub 2018 Nov 22.

Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229ER, Maastricht, Netherlands; Institute of General Pathology and Pathophysiology, Baltiiskaya str, 8, Moscow 125315, Russia; Sechenov First Moscow State Medical University, Institute of Molecular Medicine, Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Trubetskaya street 8-2, 119991, Moscow, Russia. Electronic address:

Emotional stress is a form of stress evoked by processing negative mental experience rather than an organic or physical disturbance and is a frequent cause of neuropsychiatric pathologies, including depression. Susceptibility to emotional stress is commonly regarded as a human-specific trait that is challenging to model in other species. Recently, we showed that a 3-week-long exposure to ultrasound of unpredictable alternating frequencies within the ranges of 20-25 kHz and 25-45 kHz can induce depression-like characteristics in laboratory mice and rats. In an anti-depressant sensitive manner, exposure decreases sucrose preference, elevates behavioural despair, increases aggression, and alters serotonin-related gene expression. To further investigate this paradigm, we studied depression/distress-associated markers of neuroinflammation, neuroplasticity, oxidative stress and the activity of glycogen synthase kinase-3 (GSK-3) isoforms in the hippocampus of male mice. Stressed mice exhibited a decreased density of Ki67-positive and DCX-positive cells in the subgranular zone of hippocampus, and altered expression of brain-derived neurotrophic factor (BDNF), its receptor TrkB, and anti-apoptotic protein kinase B phosphorylated at serine 473 (AktpSer473). The mice also exhibited increased densities of Iba-1-positive cells, increased oxidative stress, increased levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) in the hippocampus and plasma, and elevated activity of GSK-3 isoforms. Together, the results of our investigation have revealed that unpredictable alternating ultrasound evokes behavioural and molecular changes that are characteristic of the depressive syndrome and validates this new and simple method of modeling emotional stress in rodents.
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http://dx.doi.org/10.1016/j.pnpbp.2018.11.014DOI Listing
March 2019

Early Growth Response Gene-2 Is Essential for M1 and M2 Macrophage Activation and Plasticity by Modulation of the Transcription Factor CEBPβ.

Front Immunol 2018 1;9:2515. Epub 2018 Nov 1.

Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.

The process of macrophage polarization is involved in many pathologies such as anti-cancer immunity and autoimmune diseases. Polarized macrophages exhibit various levels of plasticity when M2/M(IL-4) macrophages are reprogrammed into an M1-like phenotype following treatment with IFNγ and/or LPS. At the same time, M1 macrophages are resistant to reprogramming in the presence of M2-like stimuli. The molecular mechanisms responsible for the macrophages polarization, plasticity of M2 macrophages, and lack of plasticity in M1 macrophages remain unknown. Here, we explored the role of Egr2 in the induction and maintenance of macrophage M1 and M2 polarization in the mouse and models of inflammation. Egr2 knockdown with siRNA treatment fail to upregulate either M1 or M2 markers upon stimulation, and the overexpression of Egr2 potentiated M1 or M2 marker expression following polarization. Polarisation with M2-like stimuli (IL-4 or IL-13) results in increased Egr2 expression, but macrophages stimulated with M1-like stimuli (IFNγ, LPS, IL-6, or TNF) exhibit a decrease in Egr2 expression. Egr2 was critical for the expression of transcription factors CEBPβ and PPARγ in M2 macrophages, and CEBPβ was highly expressed in M1-polarized macrophages. In siRNA knockdown studies the transcription factor CEBPβ was found to negatively regulate Egr2 expression and is likely to be responsible for the maintenance of the M1-like phenotype and lack plasticity. During thioglycolate-induced peritonitis, adoptively transferred macrophages with Egr2 knockdown failed to become activated as determined by upregulation of MHC class II and CD86. Thus, our study indicates that Egr2 expression is associated with the ability of unstimulated or M2 macrophages to respond to stimulation with inflammatory stimuli, while low levels of Egr2 expression is associated with non-responsiveness of macrophages to their activation.
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http://dx.doi.org/10.3389/fimmu.2018.02515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221966PMC
October 2019

Platelets mediate protective neuroinflammation and promote neuronal plasticity at the site of neuronal injury.

Brain Behav Immun 2018 11 11;74:7-27. Epub 2018 Sep 11.

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin N.T., Hong Kong; Kunming Institute of Zoology and Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunmin-Hong Kong, China. Electronic address:

It is generally accepted that inflammation within the CNS contributes to neurodegeneration after traumatic brain injury (TBI), but it is not clear how inflammation is initiated in the absence of infection and whether this neuroinflammation is predominantly beneficial or detrimental. We have previously found that brain-enriched glycosphingolipids within neuronal lipid rafts (NLR) induced platelet degranulation and secretion of neurotransmitters and pro-inflammatory factors. In the present study, we compared TBI-induced inflammation and neurodegeneration in wild-type vs. St3gal5 deficient (ST3) mice that lack major CNS-specific glycosphingolipids. After TBI, microglial activation and CNS macrophage infiltration were substantially reduced in ST3 animals. However, ST3 mice had a larger area of CNS damage with marked neuronal/axonal loss. The interaction of platelets with NLR stimulated neurite growth, increased the number of PSD95-positive dendritic spines, and intensified neuronal activity. Adoptive transfer and blocking experiments provide further that platelet-derived serotonin and platelet activating factor plays a key role in the regulation of sterile neuroinflammation, hemorrhage and neuronal plasticity after TBI.
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http://dx.doi.org/10.1016/j.bbi.2018.09.009DOI Listing
November 2018

Plasma Nuclear Magnetic Resonance Metabolomics Discriminates Between High and Low Endoscopic Activity and Predicts Progression in a Prospective Cohort of Patients With Ulcerative Colitis.

J Crohns Colitis 2018 Nov;12(11):1326-1337

Department of Pharmacology, University of Oxford, Oxford, UK.

Background And Aims: Endoscopic assessment of ulcerative colitis [UC] is one of the most accurate measures of disease activity, but frequent endoscopic investigations are disliked by patients and expensive for the healthcare system. A minimally invasive test that provides a surrogate measure of endoscopic activity is required.

Methods: Plasma nuclear magnetic resonance [NMR] spectra from 40 patients with UC followed prospectively over 6 months were analysed with multivariate statistics. NMR metabolite profiles were compared with endoscopic [Ulcerative Colitis Endoscopic Index of Severity: UCEIS], histological [Nancy Index] and clinical [Simple Clinical Colitis Activity Index: SCCAI] severity indices, along with routine blood measurements.

Results: A blinded principal component analysis spontaneously separated metabolite profiles of patients with low [≤3] and high [>3] UCEIS. Orthogonal partial least squares discrimination analysis identified low and high UCEIS metabolite profiles with an accuracy of 77 ± 5%. Plasma metabolites driving discrimination included decreases in lipoproteins and increases in isoleucine, valine, glucose and myo-inositol in high compared to low UCEIS. This same metabolite profile distinguished between low [Nancy 0-1] and high histological activity [Nancy 3-4] with a modest although significant accuracy [65 ± 6%] but was independent of SCCAI and all blood parameters measured. A different metabolite profile, dominated by changes in lysine, histidine, phenylalanine and tyrosine, distinguished between improvement in UCEIS [decrease ≥1] and worsening [increase ≥1] over 6 months with an accuracy of 74 ± 4%.

Conclusion: Plasma NMR metabolite analysis has the potential to provide a low-cost, minimally invasive technique that may be a surrogate for endoscopic assessment, with predictive capacity.
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http://dx.doi.org/10.1093/ecco-jcc/jjy101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403054PMC
November 2018
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