neuroinflammation – Page 6 – American ME and CFS Society

Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine

Abstract:

The diagnosis of chronic fatigue syndrome (CFS) is mainly symptom-based, and the etiology is still unclear. Here, we evaluated the pathological changes in the brain of a mouse model of CFS and studied the effects of Kampo medicine.

A mouse model of CFS was established through six repeated injections of Brucella abortus (BA) every two weeks for a period of 12 weeks. Neuroinflammation was measured by estimating interleukin (IL)-1β, IL-6, and interferon-gamma (IFN-γ), and oxidative stress by nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) 6 weeks after the last injection. Hippocampal neurogenesis was evaluated through Ki-67, doublecortin (DCX), and 5-bromodeoxyuridine (BrdU) assays. The effects of Kampo medicines (Hochuekkito (TJ-41) and Hachimijiogan (TJ-7)) on neuroinflammation during CFS were studied.

The wheel-running activity of mice was decreased by about 50% compared to baseline at 6 weeks after the last BA injection. The levels of IL-1β, IL-6, 3-NT, and 4-HNE were increased in both the cortex and the hippocampus of CFS mice at 6 weeks after the last BA injection. Hippocampal neurogenesis was unchanged in CFS mice. Treatment with TJ-41 and TJ-7 reduced the expressions of IL-1β, IL-6, and IFN-γ in the hippocampus but not in the cortex.

The results of the present study indicate that neuroinflammation and oxidative stress play important roles in the pathogenesis of CFS. The data further suggest that treatment with TJ-41 and TJ-7 could help reduce the inflammation associated with CFS in the hippocampus, but failed to improve the symptoms in CFS mice.

Source: He Q, Sawada M, Yamasaki N, Akazawa S, Furuta H, Uenishi H, Meng X, Nakahashi T, Ishigaki Y, Moriya J. Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine. Biol Pharm Bull. 2020;43(1):110-115. doi: 10.1248/bpb.b19-00616. https://www.jstage.jst.go.jp/article/bpb/43/1/43_b19-00616/_article (Full article)

Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination?

Abstract:

Fibromyalgia is a disorder characterized by chronic widespread pain and non-pain symptoms, such as fatigue, dysautonomia, and cognitive and sleep disturbances. Its pathogenesis and treatment continue to be the subject of debate. We highlight the role of three mechanisms-autoimmunity, neuroinflammation, and small fiber neuropathy in the pathogenesis of the disease. These mechanisms are shown to be closely interlinked (also on a molecular level), and the review considers the implementation of this relationship in the search for therapeutic options.

We also pay attention to chronic fatigue syndrome, which overlaps with fibromyalgia, and propose a concept of “autoimmune hypothalamopathy” for its pathogenesis. Finally, we analyze the molecular mechanisms underlying the neuroinflammatory background in the development of adverse events following HPV vaccination and suggesting neuroinflammation, which could exacerbate the development of symptoms following HPV vaccination (though this is hotly debated), as a model for fibromyalgia pathogenesis.

Source: Ryabkova VA, Churilov LP, Shoenfeld Y. Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination? Int J Mol Sci. 2019 Oct 18;20(20). pii: E5164. doi: 10.3390/ijms20205164. https://www.mdpi.com/1422-0067/20/20/5164 (Full article)

Neuroinflammation disorders exacerbated by environmental stressors

Abstract:

Neuroinflammation is a condition characterized by the elaboration of proinflammatory mediators within the central nervous system. Neuroinflammation has emerged as a dominant theme in contemporary neuroscience due to its association with neurodegenerative disease states such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

While neuroinflammation often is associated with damage to the CNS, it also can occur in the absence of neurodegeneration, e.g., in association with systemic infection. The “acute phase” inflammatory response to tissue injury or infections instigates neuroinflammation-driven “sickness behavior,” i.e. a constellation of symptoms characterized by loss of appetite, fever, muscle pain, fatigue and cognitive problems. Typically, sickness behavior accompanies an inflammatory response that resolves quickly and serves to restore the body to homeostasis. However, recurring and sometimes chronic sickness behavior disorders can occur in the absence of an underlying cause or attendant neuropathology.

Here, we review myalgic enchepalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Illness (GWI), and chemobrain as examples of such disorders and propose that they can be exacerbated and perhaps initiated by a variety of environmental stressors. Diverse environmental stressors may disrupt the hypothalamic pituitary adrenal (HPA) axis and contribute to the degree and duration of a variety of neuroinflammation-driven diseases.

Source: O’Callaghan JP, Miller DB. Neuroinflammation disorders exacerbated by environmental stressors. Metabolism. 2019 Nov;100S:153951. doi: 10.1016/j.metabol.2019.153951. https://www.ncbi.nlm.nih.gov/pubmed/31610852

Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians.

There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness. Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2-3 years that promise new leads towards an effective clinical diagnostic test that may have a general application.

Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness. These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.

Source: Sweetman E, Noble A, Edgar C, Mackay A, Helliwell A, Vallings R, Ryan M, Tate W. Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Diagnostics (Basel). 2019 Jul 10;9(3). pii: E73. doi: 10.3390/diagnostics9030073. https://www.mdpi.com/2075-4418/9/3/73 (Full article)

Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

PURPOSE: Neuroinflammation is a common feature in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), affecting 85%-90% of all patients, yet the underlying mechanism or mechanisms responsible for the initiation and/or promotion of this process is largely unknown. Multiple reports, however, have suggested a role for Epstein-Barr virus (EBV), in particular, in ME/CFS, but its potential role, if any, in the neuroinflammatory process has not been addressed. In support of this premise, studies by our group have found that the EBV protein deoxyuridine triphosphate nucleotidohydrolase (dUTPase) induces anxiety and sickness behaviors in female mice. We also found that a small subset of patients with ME/CFS exhibited prolonged and significantly elevated neutralizing antibodies against EBV dUTPase protein in serum, which inversely correlated with ME/CFS symptoms. A larger ME/CFS case-control cohort study further confirmed that a significant percentage of patients with ME/CFS (30.91%-52.7%) were simultaneously producing antibodies against multiple human herpesviruses-encoded dUTPases and/or human dUTPase. Altogether, these findings suggest that EBV dUTPase protein may be involved in the neuroinflammatory process observed in ME/CFS. Thus, the aim of the present study was to determine whether the EBV dUTPase protein could contribute to neuroinflammation by altering the expression of genes involved with maintaining blood-brain barrier (BBB) integrity and/or modulating synaptic plasticity.

METHODS: With the use of human immortalized astrocytes, microglia, and cerebral microvascular endothelial cells, we conducted time-course (0-24 h) experiments with EBV dUTPase protein (10 μg/mL) to determine what effect(s) it may have on the expression of genes involved with BBB permeability, astrocytes and microglia cell function, tryptophan metabolism, and synaptic plasticity by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In parallel, in vivo studies were conducted in female C57Bl/6 mice. Mice were injected by the intraperitoneal route with EBV dUTPase protein (10 μg) or vehicle daily for 5 days, and the brains were collected and processed for further qRT-PCR analysis of the in vivo effect of the dUTPase on the dopamine/serotonin and γ-aminobutyric acid/glutamate pathways, which are important for brain function, using RT2 Profiler PCR Arrays.

FINDINGS: EBV dUTPase protein altered the expression in vitro (12 of 15 genes and 32 of 1000 proteins examined) and in vivo (34 of 84 genes examined) of targets with central roles in BBB integrity/function, fatigue, pain synapse structure, and function, as well as tryptophan, dopamine, and serotonin metabolism.

IMPLICATIONS: The data suggest that in a subset of patients with ME/CFS, the EBV dUTPase could initiate a neuroinflammatory reaction, which contributes to the fatigue, excessive pain, and cognitive impairments observed in these patients.

Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome

Abstract:

BACKGROUND: Patients diagnosed with chronic fatigue syndrome (CFS) or fibromyalgia experience chronic pain. Concomitantly, the rat model of CFS exhibits microglial activation in the lumbar spinal cord and pain behavior without peripheral tissue damage and/or inflammation. The present study addressed the mechanism underlying the association between pain and chronic stress using this rat model.

METHODS: Chronic or continuous stress-loading (CS) model rats, housed in a cage with a thin level of water (1.5 cm in depth), were used. The von Frey test and pressure pain test were employed to measure pain behavior. The neuronal and microglial activations were immunohistochemically demonstrated with antibodies against ATF3 and Iba1. Electromyography was used to evaluate muscle activity.

RESULTS: The expression of ATF3, a marker of neuronal hyperactivity or injury, was first observed in the lumbar dorsal root ganglion (DRG) neurons 2 days after CS initiation. More than 50% of ATF3-positive neurons simultaneously expressed the proprioceptor markers TrkC or VGluT1, whereas the co-expression rates for TrkA, TrkB, IB4, and CGRP were lower than 20%. Retrograde labeling using fluorogold showed that ATF3-positive proprioceptive DRG neurons mainly projected to the soleus. Substantial microglial accumulation was observed in the medial part of the dorsal horn on the fifth CS day. Microglial accumulation was observed around a subset of motor neurons in the dorsal part of the ventral horn on the sixth CS day. The motor neurons surrounded by microglia were ATF3-positive and mainly projected to the soleus. Electromyographic activity in the soleus was two to three times higher in the CS group than in the control group. These results suggest that chronic proprioceptor activation induces the sequential activation of neurons along the spinal reflex arc, and the neuronal activation further activates microglia along the arc. Proprioceptor suppression by ankle joint immobilization significantly suppressed the accumulation of microglia in the spinal cord, as well as the pain behavior.

CONCLUSION: Our results indicate that proprioceptor-induced microglial activation may be a key player in the initiation and maintenance of abnormal pain in patients with CFS.

Source: Yasui M, Menjyo Y, Tokizane K, Shiozawa A, Tsuda M, Inoue K, Kiyama H. Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome. J Neuroinflammation. 2019 Mar 30;16(1):67. doi: 10.1186/s12974-019-1456-x. https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1456-x (Full article)

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the label given to a syndrome that can include long-term flu-like symptoms, profound fatigue, trouble concentrating, and autonomic problems, all of which worsen after exertion. It is unclear how many individuals with this diagnosis are suffering from the same condition or have the same underlying pathophysiology, and the discovery of biomarkers would be clarifying.

The name “myalgic encephalomyelitis” essentially means “muscle pain related to central nervous system inflammation” and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement.

The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: (1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand (2) magnetic resonance spectroscopy (MRS) neuroimaging and (3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation. However, methodological difficulties that exist both in this particular technique and across the ME/CFS neuroimaging literature must be addressed for any results to be interpretable.

We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine “profile” for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies.

We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.

Source: Michael B. VanElzakker, Sydney A. Brumfield and Paula S. Lara Mejia. Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods. Front. Neurol., 10 January 2019 | https://doi.org/10.3389/fneur.2018.01033 https://www.frontiersin.org/articles/10.3389/fneur.2018.01033/full?fbclid=IwAR3KxhofUaLakZRPNiyBliNHSlJvUOdsVqVf5cED_i6o5gF9MCbWxpeS298#h7 (Full article)

Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy

Abstract:

Previous neuroimaging studies have detected markers of neuroinflammation in patients with Myalgic Encephalomyelitis /ChronicFatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain.

Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI). Choline (CHO), myo-inositol (MI),lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), and compared between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups.

Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.

Source: Christina Mueller, Joanne C. Lin, Sulaiman Sheriff, Andrew A. Maudsley, Jarred W. Younger. Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging and Behavior. https://link.springer.com/epdf/10.1007/s11682-018-0029-4?author_access_token=rNZAi4Qn9MGbc1YywGoHCve4RwlQNchNByi7wbcMAY4otkELpwVAg-M9CJyul_kO-cT6SC717CxfcGOGfesdx7f1AhmYrPeCJukInpp-Dq7L6ew7TkRsW7LllmoDMoo7GAglGA7edR1iMan4xy8-LA%3D%3D (Full article)

VIDEO: Jarred Younger, PhD | How Brain Inflammation Causes ME/CFS

Jarred Younger studied Psychophysiology at the University of Tennessee in Knoxville in 2003. He then completed postdoctoral fellowships in pain medicine and neuroimaging at Arizona State University and Stanford University before joining the faculty at Stanford in 2009. In 2014, he transferred to the University of Alabama at Birmingham, where he currently directs the Neuroinflammation, Pain and Fatigue Laboratory. His lab uses neuroimaging, immune monitoring, and clinical trial techniques to develop new diagnostic tests and treatments for pain and fatigue disorders.

You can read the full transcript HERE.

A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS

[Editor’s comment: While nicely explored in this article, the idea that the limbic system is the main driver behind ME/CFS symptoms is hardly new. Jay Goldstein in his 286-page book, Chronic Fatigue Syndromes: The Limbic Hypothesis (June 1993), examines the important role of the limbic system, and in particular the hypothalamus, in ME/CFS pathophysiology. The authors of this article fail to give him a mention.]

Abstract:

A neuroinflammatory paradigm is presented to help explain the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The hypothalamic paraventricular nucleus (PVN) is responsible for absorbing and processing multiple, incoming and convergent ‘stress’ signals, and if this cluster of neurons were affected (by neuroinflammation), the ongoing hypersensitivity of ME/CFS patients to a wide range of ‘stressors’ could be explained. Neuroinflammation that was chronic and fluctuating, as ‘inflammatory-marker’ studies support, could reflect a dynamic change in the hypothalamic PVN’s threshold for managing incoming ‘stress’ signals.

This may not only be a mechanism underpinning the characteristic feature of ME/CFS, post-exertional malaise, and its associated debilitating relapses, but could also be responsible for mediating the long-term perpetuation of the disease. Triggers (sustained physiological ‘stressors’) of ME/CFS, such as a particular viral infection, toxin exposure, or a traumatic event, could also target the hypothalamic PVN, a potentially vulnerable site in the brains of ME/CFS susceptible people, and disruption of its complex neural circuitry could account for the onset of ME/CFS. In common with the different ‘endogenous factors’ identified in the early ‘neuroinflammatory’ stages of the ‘neurodegenerative’ diseases, an as yet, unidentified factor within the brains and central nervous system (CNS) of ME/CFS patients might induce both an initial and then sustained ‘neuroinflammatory’ response by its ‘innate immune system’.

Positron emission tomography/magnetic resonance imaging has reinforced evidence of glial cell activation centred on the brain’s limbic system of ME/CFS patients. Neuroinflammation causing dysfunction of the limbic system and its hypothalamus together with a consequently disrupted autonomic nervous system could account for the diverse range of symptoms in ME/CFS relating, in particular to fatigue, mood, cognitive function, sleep, thermostatic control, gastrointestinal disturbance, and hypotension.

Source: Angus Mackay, Warren P Tate. A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS. International Journal of Immunopathology and Pharmacology. First Published December 6, 2018. https://doi.org/10.1177/2058738418812342 https://journals.sagepub.com/doi/full/10.1177/2058738418812342 (Full article)