Chronic Fatigue Syndrome (CFS) is a complex disease with a prevalence as high as 1%. CFS involves the nervous, hormonal and immune systems with symptoms that include fatigue, sleep disturbances, malaise, muscle aches, migraines, gastrointestinal complaints and cognitive problems. There may be some mitochondrial """"""""dysfunction"""""""" in CFS patients. Many CFS patients demonstrate abnormal hypothalamic-pituitary- adrenal (HPA) axis activity, while stress worsens symptoms. Central and peripheral cytokines produced in response to viral infections or other inflammatory stimuli may be implicated, but there is no distinct pattern. CFS is often comorbid with other disorders that include fibromyalgia, interstitial cystitis (1C), irritable bowel syndrome (IBS), migraines and post-traumatic stress disorder. Neuroimmune interactions in CFS are still unknown creating a vacuum in diagnosis and treatment. Mast cells and their mediators have been implicated in all diseases that are comorbid with CFS. Brain mast cells are abundant in the median eminence where they are juxtaposed to corticotropin-releasing hormone (CRH)-positive neurons and CRH is secreted under stress and we showed that CRH activates mast cells through CRHR-1 leading to release of vascular endothelial growth factor (VEGF), increased vascular permeability and blood-brain-barrier (BBB) disruption. We recently showed an inverse relationship between expression of the mitochondrial uncoupling protein 2 (UCP2), which also regulates production of reactive oxygen species (ROS) and cytosolic calcium, and mast cell activation. There are no effective therapies for CFS. Tricyclic antidepressants have been reported to be beneficial, and our preliminary results indicate that only the tricyclic amitriptyline, and certain natural flavonoids can inhibit mast cell secretion and reduce intracellular calcium ion levels. Our hypothesis is that external triggers, along with CRH secreted by stress, activate diencephalic centers and mast cells, leading to release of proinflammatory and fatigue producing molecules, and these can be inhibited by select flavonoids. We will investigate: (1) the effect of CRH, viral poly(l:C), lipopolysaccharide (LPS), neurotensin (NT), substance P (SP) and thymus stromal lymphopoietin (TSMP) or restraint stress using female C57BL/6 mice on: (a) Fatigue using the forced water immersion test, (b) BBB disruption by measuring brain levels of the fluorescent marker AngioSense, as well as (c) Brain expression of histidine decarboxylase (HDC), CRN, beta-endorphin, IL-6, IL- 8, IL-17, somatostatin, TNF, mouse mast cell protease (MMCP), urocortin 2, UCP2 and VEGF;(2) The requirement for mast cells, for NT, SP, the CRHR involved, and the role of UCP2 in the endpoints studied in Aim 1 by using C57BL-derived WW mast cell deficient mice, NT -/- mice, SP -/- mice, CRHR-1;CRHR-2 -/- and UCP2 -/- mice, (3) Inhibitory effect of a flavonoid formulation containing luteolin/quercetin/olive kernel oil on endurance and brain biomarkers. The proposed research is hypothesis-driven, is based on strong preliminary evidence, is innovative with high likelihood for novel findings with applicability to humans.

Public Health Relevance

Chronic Fatigue Syndrome (CFS) is neuroimmunoendocrine disorder with no definite pathogenesis or curative therapy presently available. Recent evidence suggests that CFS may be related to activation of a unique immune cell, the mast cell, which could disrupt gut-blood-brain barrier and lead to brain inflammation and release of fatigue causing molecules. The proposed research is expected to advance our understanding of how activation of brain mast cells can contribute to inflammation and CFS, as well as to the development of novel and effective treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS071361-02
Application #
8090275
Study Section
Special Emphasis Panel (ZRG1-CFS-M (90))
Program Officer
Mitler, Merrill
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$350,036
Indirect Cost
Name
Tufts University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Vasiadi, Magdalini; Newman, Jennifer; Theoharides, Theoharis C (2014) Isoflavones inhibit poly(I:C)-induced serum, brain, and skin inflammatory mediators - relevance to chronic fatigue syndrome. J Neuroinflammation 11:168
Petra, Anastasia I; Panagiotidou, Smaro; Stewart, Julia M et al. (2014) Spectrum of mast cell activation disorders. Expert Rev Clin Immunol 10:729-39
Alevizos, Michail; Karagkouni, Anna; Panagiotidou, Smaro et al. (2014) Stress triggers coronary mast cells leading to cardiac events. Ann Allergy Asthma Immunol 112:309-16
Theoharides, Theoharis C; Asadi, Shahrzad; Panagiotidou, Smaro et al. (2013) The ""missing link"" in autoimmunity and autism: extracellular mitochondrial components secreted from activated live mast cells. Autoimmun Rev 12:1136-42
Papathanasiou, E; Palaska, I; Theoharides, T C (2013) Stress hormones regulate periodontal inflammation. J Biol Regul Homeost Agents 27:621-6
Sismanopoulos, N; Delivanis, D-A; Mavrommati, D et al. (2013) Do mast cells link obesity and asthma? Allergy 68:8-15
Sismanopoulos, Nikolaos; Delivanis, Danae-Anastasia; Alysandratos, Konstantinos-Dionysios et al. (2012) Mast cells in allergic and inflammatory diseases. Curr Pharm Des 18:2261-77
Theoharides, Theoharis C; Alysandratos, Konstantinos-Dionysios; Angelidou, Asimenia et al. (2012) Mast cells and inflammation. Biochim Biophys Acta 1822:21-33
Theoharides, Theoharis C; Sismanopoulos, Nikolaos; Delivanis, Danae-Anastasia et al. (2011) Mast cells squeeze the heart and stretch the gird: their role in atherosclerosis and obesity. Trends Pharmacol Sci 32:534-42