Inhibitory Effects of Isoflavones on Mouse Inflammatory Mediators and Relevance to Chronic Fatigue Syndrome.
Chronic fatigue syndrome (CFS) is a complex, heterogeneous disease affecting more than
one million Americans, mostly women. Despite extensive research, no definitive cause has
been determined, even though some evidence suggests an infectious etiology. Many CFS
patients demonstrate abnormal hypothalamic-pituitary-adrenal (HPA) axis activity and
high anxiety. Corticotropin-re... read moreleasing hormone (CRH) and neurotensin (NT), secreted under
stress, could activate mast cells (MC), which are involved in comorbid diseases with
CFS, such as fibromyalgia, to release inflammatory mediators contributing to CFS
symptoms. Abnormal overexpression of MC has been linked to skin hypersensitivity in
fibromyalgia patients. Most current murine "models" of CFS use forced swim daily for
7-43 days, with or without an immunological trigger, including lipopolysaccharide (LPS)
and/or polyinosinic:polycytidylic acid [poly(I:C)], to induce "chronic fatigue,"
assessed by behavioral and biochemical parameters. I used C57BL/6 and/or BALB/c mice,
subjected to forced swim, daily for up to twenty one days, with or without LPS or
poly(I:C), which did not result in chronic fatigue, as reported previously by similar
studies on albino LACA mice. Fatigue symptoms in either C57BL/6 or BALB/c mice were
present only for the first three days and were best documented by decreased locomotor
activity. Poly(I:C) treatment decreased mouse locomotor activity and increased
inflammatory mediator levels in the serum, as well as their brain and skin expression.
High isoflavone diet (daidzein, genistein) reversed these effects. Poly(I:C) alone
increased tumor necrosis factor (TNF) gene expression in cultured MC, and when used
together with CRH, NT or substance P (SP), for 24 hours (hr), TNF gene expression was
significantly enhanced. To circumvent the challenge of obtaining skin biopsies from CFS
patients, I analyzed skin and serum samples from atopic dermatitis (AD) and psoriasis
(PS) patients, who exhibit similar skin sensitivity as CFS patients. I demonstrated that
NT and CRH serum levels are increased in patients with both diseases, as is NT gene
expression in affected skin from AD patients. NTR-1 skin gene expression in AD patients
was unchanged, while NT and NTR-1 skin gene expression in PS patients, as well as CRHR-1
skin gene expression in AD and PS patients, were reduced suggesting downregulation. High
expression of NT and CRH in the serum and skin of AD and serum of PS patients, and
increase in TNF gene expression after stimulation of human cultured MC with NT and CRH,
suggest that these peptides, which are secreted under stress, could activate MC to
release inflammatory mediators contributing to CFS symptoms. In summary, poly(I:C)
treatment induced "fatigue behavior" after 24 hr which was reversed by isoflavones known
to inhibit MC.
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: Theoharis Theoharides.
Committee: Laura Liscum, John Castellot, David Cochrane, and Benjamin Natelson.
Keyword: Pharmacology.read less