Category: Pathophysiology

Cellular and molecular mechanisms of interaction between the neuroendocrine and immune systems under chronic fatigue syndrome in experiment

Abstract:

One of the main mechanisms of chronic fatigue syndrome development involves disturbances of interaction between the immune and neuroendocrine systems. The adequate experimental model for the search of these mechanisms is induction of fatigue in animals via the single intraperitoneal administration of synthetic double-stranded RNA – Poly I : C.

Investigation of alterations in cytotoxic and proliferation activities of splenocytcs, the intensity of immunomodulatory cytokines signaling via the sphingomyelin pathways in membrane P2 fraction of the brain cortex, as well as the activity of hypothalamic-pituitary adrenal (HP A) axis in the dynamics of chronic fatigue syndrome in rats has performed. Inhibition of both cytotoxic and proliferative activities of splenocytes during the period of fatigue development has been shown. Priority data concerning the suppression of the activity of neutral sphingomyelinase (nSMase) – the key enzyme of the sphingomyelin cascade – in membranes ofthe cells from the brain cortex on the 3d day after Poly I : C administration to rats have been obtained.

It was found that Poly I : C injection to rats led to disturbed HPA axis functions which was manifested by decreased corticosterone concentration in standard functional assays with ACTH and hydrocortisone administration.

It is suggested that disturbances in interaction between the immune and neuroendocrine systems during development of chronic fatigue syndrome, including alterations in HPA axis activity, are realized both on the level of changes in the activity of immune-competent cells and immediately on membranes of the brain cells.

 

Source: Rybakina EG, Shanin SN, Fomicheva EE, Korneva EA. Cellular and molecular mechanisms of interaction between the neuroendocrine and immune systems under chronic fatigue syndrome in experiment. Ross Fiziol Zh Im I M Sechenova. 2009 Dec;95(12):1324-35. [Article in Russian] https://www.ncbi.nlm.nih.gov/pubmed/20141043

 

Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS

Abstract:

There is evidence that disorders in inflammatory and oxidative and nitrosative (IO&NS) pathways and a lowered antioxidant status are important pathophysiological mechanisms underpinning myalgic encephalomyelitis / chronic fatigue syndrome(ME/CFS). Important precipitating and perpetuating factors for ME/CFS are (amongst others) bacterial and viral infections; bacterial translocation due to an increased gut permeability; and psychological stress.

Recently, Jason et al (2006) reported that the mean age of patients with myalgic encephalomyelitis/chronic fatigue syndrome dying from heart failure, i.e. 58.7 years, is significantly lower than the age of those dying from heart failure in the general US population, i.e. 83.1 years. These findings implicate that ME/CFS is a risk factor to cardio-vascular disorder.

This review demonstrates that disorders in various IO&NS pathways provide explanations for the earlier mortality due to cardiovascular disorders in ME/CFS. These pathways are: a) chronic low grade inflammation with extended production of nuclear factor kappa B and COX-2 and increased levels of tumour necrosis factor alpha; b) increased O&NS with increased peroxide levels, and phospholipid oxidation including oxidative damage to phosphatidylinositol; c) decreased levels of specific antioxidants, i.e. coenzyme Q10, zinc and dehydroepiandrosterone-sulphate; d) bacterial translocation as a result of leaky gut; e) decreased omega-3 polyunsatutared fatty acids (PUFAs), and increased omega-6 PUFA and saturated fatty acid levels; and f) the presence of viral and bacterial infections and psychological stressors. The mechanisms whereby each of these factors may contribute towards cardio-vascular disorder in ME/CFS are discussed.

ME/CFS is a multisystemic metabolic-inflammatory disorder. The aberrations in IO&NS pathways may increase the risk for cardiovascular disorders.

 

Source: Maes M, Twisk FN. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. 2009;30(6):677-93. https://www.ncbi.nlm.nih.gov/pubmed/20038921

 

Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis / chronic fatigue syndrome

Abstract:

BACKGROUND: There is now evidence that major depression and myalgic encephalomyelitis / chronic fatigue syndrome(ME/CFS) are accompanied by partially overlapping pathophysiological mechanisms, i.e. activation of various inflammatory and oxidative & nitrosative (IO&NS) pathways.

OBJECTIVE: The aim of the present study was to examine the urinary excretion of 8-hydroxy-deoxyguanosine (8-OhdG), a marker of oxidative damage to DNA, in depression; ME/CFS; and depression and ME/CFS.

METHODS: Toward this end, morning urine was sampled for the assays of 8-OHdG and creatinine, in 44 patients with ME/CFS; 25 with major depression; 23 with depression and ME/CFS; and 17 normal controls. Severity of fatigue and somatic symptoms was measured by means of the Fibromyalgia and CFS Rating (FF) scale.

RESULTS: We found that 49.0% of the variance in the urinary excretion of 8-OHdG was predicted by the regression on creatinine. Consequently, the urinary 8-OHdG excretion should be expressed as the residualized 8-OHdG values after partialling out the effects of creatinine and not by computing the 8-OHdG / creatinine ratio. We found that the residualized urinary excretion of 8-OHdG (adjusted for creatinine) was significantly higher in patients with depression and ME/CFS than in normal controls and all other patients. In the patient group, there were significant correlations between the urinary 8-OHdG and the total score on the FF scale and sadness and flu-like malaise.

CONCLUSIONS: The findings show increased oxidatively generated DNA damage in patients with major depression and ME/CFS and, therefore, further extent the role played by IO&NS pathways in the pathophysiology of both disorders. Since oxidatively damage to DNA is a risk factor for atherosclerosis and neurodegeneration, our results also explain previous findings on increased cardiovascular morbidity in depression and ME/CFS, and neurodegenerative processes in depression.

 

Source: Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis / chronic fatigue syndrome. Neuro Endocrinol Lett. 2009;30(6):715-22. https://www.ncbi.nlm.nih.gov/pubmed/20035260

 

Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue?

Abstract:

Cancer and chronic fatigue syndrome (CFS) are both characterised by fatigue and severe disability. Besides fatigue, certain aspects of immune dysfunctions appear to be present in both illnesses. In this regard, a literature review of overlapping immune dysfunctions in CFS and cancer is provided.

Special emphasis is given to the relationship between immune dysfunctions and fatigue. Abnormalities in ribonuclease (RNase) L and hyperactivation of nuclear factor kappa beta (NF-kappaB) are present in CFS and in prostate cancer. Malfunctioning of natural killer (NK) cells has long been recognised as an important factor in the development and reoccurrence of cancer, and has been documented repeatedly in CFS patients.

The dysregulation of the RNase L pathway, hyperactive NF-kappaB leading to disturbed apoptotic mechanisms and oxidative stress or excessive nitric oxide, and low NK activity may play a role in the two diseases and in the physiopathology of the common symptom fatigue. However, in cancer the relation between the immune dysfunctions and fatigue has been poorly studied. Immunological abnormalities to such as a dysregulated RNase L pathway, hyperactive NF-kappaB, increased oxidative stress and reduced NK cytotoxicity, among others, are present in both diseases.

These anomalies may be part of the physiopathology of some of the common complaints, such as fatigue. Further studies to confirm the hypotheses given here are warranted.

 

Source: Meeus M, Mistiaen W, Lambrecht L, Nijs J. Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res. 2009 Nov;29(11):4717-26. http://ar.iiarjournals.org/content/29/11/4717.long (Full article)

 

Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder

Abstract:

INTRODUCTION: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medical illness characterized by disorders in inflammatory and oxidative and nitrosative (IO&NS) pathways.

METHODS: This paper examines the role of Coenzyme Q10 (CoQ10), a mitochondrial nutrient which acts as an essential cofactor for the production of ATP in mitochondria and which displays significant antioxidant activities. Plasma CoQ10 has been assayed in 58 patients with ME/CFS and in 22 normal controls; the relationships between CoQ10 and the severity of ME/CFS as measured by means of the FibroFatigue (FF) scale were measured.

RESULTS: Plasma CoQ10 was significantly (p=0.00001) lower in ME/CFS patients than in normal controls. Up to 44.8% of patients with ME/CFS had values beneath the lowest plasma CoQ10 value detected in the normal controls, i.e. 490 microg/L. In ME/CFS, there were significant and inverse relationships between CoQ10 and the total score on the FF scale, fatigue and autonomic symptoms. Patients with very low CoQ10 (<390 microg/L) suffered significantly more from concentration and memory disturbances.

DISCUSSION: The results show that lowered levels of CoQ10 play a role in the pathophysiology of ME/CFS and that symptoms, such as fatigue, and autonomic and neurocognitive symptoms may be caused by CoQ10 depletion. Our results suggest that patients with ME/CFS would benefit from CoQ10 supplementation in order to normalize the low CoQ10 syndrome and the IO&NS disorders. The findings that lower CoQ10 is an independent predictor of chronic heart failure (CHF) and mortality due to CHF may explain previous reports that the mean age of ME/CFS patients dying from CHF is 25 years younger than the age of those dying from CHF in the general population. Since statins significantly decrease plasma CoQ10, ME/CFS should be regarded as a relative contraindication for treatment with statins without CoQ10 supplementation.

 

Source: Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009;30(4):470-6. https://www.ncbi.nlm.nih.gov/pubmed/20010505

 

Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness

Abstract:

INTRODUCTION: There is now evidence that major depression is accompanied by an induction of inflammatory and oxidative and nitrosative stress (IO&NS) pathways and by a lowered antioxidant status. Coenzyme Q10 (CoQ10) is a strong antioxidant that has anti-inflammatory effects.

METHODS: This paper examines the plasma concentrations of CoQ10 in 35 depressed patients and 22 normal volunteers and the relationships between plasma CoQ10 and treatment resistant depression (TRD), the severity of illness as measured by means of the Hamilton Depression Rating Scale (HDRS) and the presence of chronic fatigue syndrome (CFS).

RESULTS: We found that plasma CoQ10 was significantly (p=0.0002) lower in depressed patients than in normal controls. 51.4% of the depressed patients had plasma CoQ10 values that were lower than the lowest plasma CoQ10 value detected in the controls. Plasma CoQ10 was significantly lower in patients with TRD and with CFS than in the other depressed patients. There were no significant correlations between plasma CoQ10 and the HDRS.

DISCUSSION: The results show that lower CoQ10 plays a role in the pathophysiology of depression and in particular in TRD and CFS accompanying depression. It is suggested that depressed patients may benefit from CoQ10 supplementation. The findings that lower CoQ10 is a risk factor to coronary artery disease and chronic heart failure (CHF) and mortality due to CHF suggest that low CoQ10 is another factor explaining the risk to cardiovascular disorder in depression. Since statins significantly lower plasma CoQ10, depressed patients and in particular those with TRD and CFS represent populations at risk to statin treatment.

 

Source: Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness. Neuro Endocrinol Lett. 2009;30(4):462-9. https://www.ncbi.nlm.nih.gov/pubmed/20010493

 

An in vivo proton neurospectroscopy study of cerebral oxidative stress in myalgic encephalomyelitis (chronic fatigue syndrome)

Abstract:

A particularly important family of antioxidant defence enzymes in the body are the glutathione peroxidases, which remove H(2)O(2) by coupling its reduction to H(2)O with oxidation of reduced glutathione (GSH) to oxidised glutathione (GSSG). There are suggestions that GSH in the peripheral blood may be reduced in myalgic encephalomyelitis, which is a highly disabling neurological disease of unknown aetiology.

Since many of the symptoms relate to cerebral functioning, it would seem probable that peripheral blood GSH findings would be reflected in lower cerebral GSH levels. The aim of this study was to carry out the first direct assessment of cerebral GSH levels in myalgic encephalomyelitis; the hypothesis being tested was that cerebral GSH levels would be reduced in myalgic encephalomyelitis.

Cerebral proton neurospectroscopy was carried out at a magnetic field strength of 3T in 26 subjects; spectra were obtained from 20x20x20mm(3) voxels using a point-resolved spectroscopy pulse sequence. The mean cerebral GSH level in the myalgic encephalomyelitis patients was 2.703 (SD 2.311) which did not differ significantly from that in age- and gender-matched normal controls who did not have any history of neurological or other major medical disorder (5.191, SD 8.984; NS). Therefore our study does not suggest that GSH is reduced in the brain in myalgic encephalomyelitis.

At the present time, based on the results of this study, there is no evidence to support the suggestion that, by taking glutathione supplements, an improvement in the brain-related symptomatology of myalgic encephalomyelitis may occur.

 

Source: Puri BK, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, Treasaden IH. An in vivo proton neurospectroscopy study of cerebral oxidative stress in myalgic encephalomyelitis (chronic fatigue syndrome). Prostaglandins Leukot Essent Fatty Acids. 2009 Nov-Dec;81(5-6):303-5. doi: 10.1016/j.plefa.2009.10.002. Epub 2009 Nov 10.https://www.ncbi.nlm.nih.gov/pubmed/19906518

 

Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects

Abstract:

Chronic fatigue syndrome (CFS) is characterized by debilitating fatigue, often accompanied by widespread muscle pain that meets criteria for fibromyalgia syndrome (FMS). Symptoms become markedly worse after exercise. Previous studies implicated dysregulation of the sympathetic nervous system (SNS), and immune system (IS) in CFS and FMS.

We recently demonstrated that acid sensing ion channel (probably ASIC3), purinergic type 2X receptors (probably P2X4 and P2X5) and the transient receptor potential vanilloid type 1 (TRPV1) are molecular receptors in mouse sensory neurons detecting metabolites that cause acute muscle pain and possibly muscle fatigue. These molecular receptors are found on human leukocytes along with SNS and IS genes.

Real-time, quantitative PCR showed that 19 CFS patients had lower expression of beta-2 adrenergic receptors but otherwise did not differ from 16 control subjects before exercise. After a sustained moderate exercise test, CFS patients showed greater increases than control subjects in gene expression for metabolite detecting receptors ASIC3, P2X4, and P2X5, for SNS receptors alpha-2A, beta-1, beta-2, and COMT and IS genes for IL10 and TLR4 lasting from 0.5 to 48 hours (P < .05). These increases were also seen in the CFS subgroup with comorbid FMS and were highly correlated with symptoms of physical fatigue, mental fatigue, and pain.

These new findings suggest dysregulation of metabolite detecting receptors as well as SNS and IS in CFS and CFS-FMS.

PERSPECTIVE: Muscle fatigue and pain are major symptoms of CFS. After moderate exercise, CFS and CFS-FMS patients show enhanced gene expression for receptors detecting muscle metabolites and for SNS and IS, which correlate with these symptoms. These findings suggest possible new causes, points for intervention, and objective biomarkers for these disorders.

 

Source: Light AR, White AT, Hughen RW, Light KC. Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. J Pain. 2009 Oct;10(10):1099-112. doi: 10.1016/j.jpain.2009.06.003. Epub 2009 Jul 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757484/ (Full article)

 

Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) are affected by symptoms of cognitive dysfunction and neurological impairment, the cause of which has yet to be elucidated. However, these symptoms are strikingly similar to those of patients presented with D-lactic acidosis.

A significant increase of Gram positive facultative anaerobic faecal microorganisms in 108 CFS patients as compared to 177 control subjects (p<0.01) is presented in this report. The viable count of D-lactic acid producing Enterococcus and Streptococcus spp. in the faecal samples from the CFS group (3.5 x 10(7) cfu/L and 9.8 x 10(7) cfu/L respectively) were significantly higher than those for the control group (5.0 x 10(6) cfu/L and 8.9 x 10(4) cfu/L respectively). Analysis of exometabolic profiles of Enterococcus faecalis and Streptococcus sanguinis, representatives of Enterococcus and Streptococcus spp. respectively, by NMR and HPLC showed that these organisms produced significantly more lactic acid (p<0.01) from (13)C-labeled glucose, than the Gram negative Escherichia coli. Further, both E. faecalis and S. sanguinis secrete more D-lactic acid than E. coli.

This study suggests a probable link between intestinal colonization of Gram positive facultative anaerobic D-lactic acid bacteria and symptom expressions in a subgroup of patients with CFS. Given the fact that this might explain not only neurocognitive dysfunction in CFS patients but also mitochondrial dysfunction, these findings may have important clinical implications.

 

Source: Sheedy JR, Wettenhall RE, Scanlon D, Gooley PR, Lewis DP, McGregor N, Stapleton DI, Butt HL, DE Meirleir KL. Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo. 2009 Jul-Aug;23(4):621-8. http://iv.iiarjournals.org/content/23/4/621.long (Full article)

 

Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study

Abstract:

Chronic fatigue syndrome (CFS) is a disabling condition characterized by unexplained chronic fatigue that impairs normal activities. Although immunological and psychological aspects are present, symptoms related to skeletal muscles, such as muscle soreness, fatigability and increased lactate accumulation, are prominent in CFS patients.

In this case-control study, the phenotype of the same biopsy samples was analyzed by determining i) fibre-type proportion using myosin isoforms as fibre type molecular marker and gel electrophoresis as a tool to separate and quantify myosin isoforms, and ii) contractile properties of manually dissected, chemically made permeable and calcium-activated single muscle fibres.

The results showed that fibre-type proportion was significantly altered in CSF samples, which showed a shift from the slow- to the fast-twitch phenotype. Cross sectional area, force, maximum shortening velocity and calcium sensitivity were not significantly changed in single muscle fibres from CSF samples. Thus, the contractile properties of muscle fibres were preserved but their proportion was changed, with an increase in the more fatigue-prone, energetically expensive fast fibre type.

Taken together, these results support the view that muscle tissue is directly involved in the pathogenesis of CSF and it might contribute to the early onset of fatigue typical of the skeletal muscles of CFS patients.

 

Source: Pietrangelo T, Toniolo L, Paoli A, Fulle S, Puglielli C, Fanò G, Reggiani C. Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study. Int J Immunopathol Pharmacol. 2009 Apr-Jun;22(2):427-36. https://www.ncbi.nlm.nih.gov/pubmed/19505395