Tag: nitric oxide

Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways

Abstract:

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels.

This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity.

Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS.

Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-α, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-β, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms.

HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.

 

Source: Morris G, Anderson G, Maes M. Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Mol Neurobiol. 2016 Oct 20. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27766535

 

Nitric oxide modulation in protective role of antidepressants against chronic fatigue syndrome in mice

Abstract:

BACKGROUND AND OBJECTIVE: The present study was designed to elucidate the possible nitric oxide (NO) mechanism in the protective effect of antidepressants using mice model of chronic fatigue syndrome (CFS).

MATERIALS AND METHODS: Male albino laca mice were forced to swim for each 6 min session for 7 days and immobility period was measured on every alternate day (1(st), 3(rd), 5(th), 7(th)). After 7 days various behavioral tests (locomotor, mirror chamber, and plus maze tests for anxiety) were performed and biochemical estimations (lipid peroxidation, nitrite levels, GSH (reduced glutathione), and catalase activity) in mice brain were performed. Animals were pretreated with citalopram (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) daily for 7 days.

RESULTS: The present study showed that continued forced swimming for 7 days caused chronic fatigue-induced anxiety-like behavior as assessed in mirror chamber, plus maze tests, and impairment in locomotor activity followed by oxidative damage (as evidenced by increased lipid peroxidation, nitrite levels, depleted reduced glutathione, and catalase activity) in animals. Seven days pretreatment with citalopram (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) significantly improved behavioral and biochemical alterations. Further, L-nitro-arginine methyl ester (L-NAME,5 mg/kg) and methylene blue (MB, 10 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) potentiated their protective effect. However, l-arginine (100 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) reversed their protective effect as compared with their effect per se (P < 0.05).

CONCLUSION: The present study suggests that protective effect of citalopram and imipramine might be due to its NO modulation against chronic fatigue induced behavioral and biochemical alterations.

 

Source: Kumar A, Garg R, Gaur V, Kumar P. Nitric oxide modulation in protective role of antidepressants against chronic fatigue syndrome in mice. Indian J Pharmacol. 2011 May;43(3):324-9. Doi: 10.4103/0253-7613.81506. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113388/ (Full article)

 

Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: a case-control study

Abstract:

AIM: since patients with chronic fatigue syndrome (CFS) often present elevated levels of nitric oxide (NO) and low levels of physical activity, this study aimed at revealing possible correlations between NO concentration and physical activity.

PATIENTS AND METHODS: thirty CFS patients and 29 age- and gender-matched sedentary controls wore an accelerometer for one week and underwent venous blood sampling at the beginning and the end of the week.

RESULTS: CFS patients were significantly less active (p=0.001), but no significant differences in the amounts of NO (p=0.464 and 0.569) or interaction between NO levels and activity levels in either the CFS patients or controls were revealed.

CONCLUSION: these results provide further evidence for reduced activity levels in CFS patients, but refute there being any interaction between the amount of blood NO and activity level in both groups. The blood NO was neither predictive of, nor dependent on the activity level in CFS.

 

Source: Meeus M, VAN Eupen I, Hondequin J, DE Hauwere L, Kos D, Nijs J. Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: a case-control study. In Vivo. 2010 Nov-Dec;24(6):865-9. https://www.ncbi.nlm.nih.gov/pubmed/21164046

 

Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: an experimental study

Abstract:

OBJECTIVE: The aims of this study were to examine: (i) baseline pressure pain thresholds in patients with chronic fatigue syndrome and those with chronic low back pain compared with healthy subjects; (ii) the change in mean pain threshold in response to exercise; and (iii) associations with exercise-induced increase in nitric oxide.

PARTICIPANTS: Twenty-six patients with chronic fatigue syndrome suffering of chronic pain, 21 patients with chronic low back pain and 31 healthy subjects.

METHODS: Participants underwent a submaximal aerobic exercise protocol on a bicycle ergometer, preceded and followed by venous blood sampling (nitric oxide) and algometry (hand, arm, calf, low back).

RESULTS: Patients with chronic fatigue syndrome presented overall lower pain thresholds compared with healthy subjects and patients with chronic low back pain (p < 0.05). No significant differences were found between healthy subjects and patients with chronic low back pain. After submaximal aerobic exercise, mean pain thresholds decreased in patients with chronic fatigue syndrome, and increased in the others (p < 0.01). At baseline, nitric oxide levels were significantly higher in the chronic low back pain group. After controlling for body mass index, no significant differences were seen between the groups at baseline or in response to exercise. Nitric oxide was not related to pain thresholds in either group.

CONCLUSION: The results suggest hyperalgesia and abnormal central pain processing during submaximal aerobic exercise in chronic fatigue syndrome, but not in chronic low back pain. Nitric oxide appeared to be unrelated to pain processing.

 

Source: Meeus M, Roussel NA, Truijen S, Nijs J. Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: an experimental study. J Rehabil Med. 2010 Oct;42(9):884-90. Doi: 10.2340/16501977-0595. https://www.medicaljournals.se/jrm/content/html/10.2340/16501977-0595 (Full article)

 

Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a disabling illness of unknown etiology that is characterized by fatigue associated with a reduced ability to work, lasting for more than 6 months, and accompanied by a specific set of symptoms. The diagnosis remains difficult because of the absence of laboratory tests and is, therefore, made largely on the basis of the symptoms reported by the patient. The aim of this study was to analyze differences in blood nitrate levels in CFS patients and a matched control group after a physical exercise test.

METHODS: Forty-four consecutive female patients with CFS and 25 healthy women performed an exercise test using a cycle ergometer with monitoring of cardiopulmonary response. Blood samples were obtained for biochemical analyses of glucose, lactate, and nitrates at the beginning (under resting conditions) and after the maximal and supramaximal tests.

RESULTS: Plasma nitrates differed between the groups, with higher values in the CFS group (F = 6.93, p = 0.003). Nitrate concentration increased in relation to workload and reached higher values in the CFS group, the maximum difference with respect to the control group being 295% (t = 4.88, p < 0.001).

CONCLUSIONS: The main result of the present study is that nitric oxide (NO) metabolites (nitrates) showed a much higher increase after a maximal physical test in CFS patients than in a group of matched subjects. This combination (exercise plus NO response evaluation) may be useful in the assessment of CFS.

 

Source: Suárez A, Guillamó E, Roig T, Blázquez A, Alegre J, Bermúdez J, Ventura JL, García-Quintana AM, Comella A, Segura R, Javierre C. Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study. J Womens Health (Larchmt). 2010 Jun;19(6):1073-7. doi: 10.1089/jwh.2008.1255. https://www.ncbi.nlm.nih.gov/pubmed/20469961

 

Nitric oxide modulation mediates the protective effect of trazodone in a mouse model of chronic fatigue syndrome

Abstract:

The present study was conducted with the aim of elucidating the possible role of nitric oxide (NO) in the neuroprotective effects of trazodone used to treat chronic fatigue syndrome (CFS) in mice.

Male albino mice were forced to swim for a six minute session each day for 7 days and the immobility period was recorded every other day. Trazodone (5 mg/kg and 10 mg/kg) was administered each day 30 min before the forced swim test. In addition, L-arginine (100 mg/kg) and L-NAME (5 mg/kg) were administered 15 min before administration of trazodone (5 mg/kg).

Various behavioral tests, including locomotor (actophotometer) and anxiety (mirror chamber and plus maze) tests, as well as biochemical parameters (lipid peroxidation, reduced glutathione, catalase, and nitrites) were evaluated on the 8th day.

Forced swimming for 7 days caused a chronic fatigue-like condition, anxiety-like behavior, impairments in locomotor activity, and oxidative damage (increased lipid peroxidation and nitrite levels, and depletions in the reduced forms of glutathione and catalase activity) in animals. Pretreatment with L-NAME (5 mg/kg) potentiated the antioxidant effect of trazodone (5 mg/kg). However, L-arginine (100 mg/kg) pretreatment reversed the protective effect of trazodone (5 mg/kg) (p<0.05). The present study suggests the possible involvement of NO signaling in the protective effect of trazodone.

 

Source: Kumar A, Garg R, Kumar P. Nitric oxide modulation mediates the protective effect of trazodone in a mouse model of chronic fatigue syndrome. Pharmacol Rep. 2008 Sep-Oct;60(5):664-72. http://www.if-pan.krakow.pl/pjp/pdf/2008/5_664.pdf (Full article)

 

Post-radiation syndrome as a NO/ONOO- cycle, chronic fatigue syndrome-like disease

Abstract:

Post-radiation syndrome is proposed to be chronic fatigue syndrome (CFS) or a chronic fatigue syndrome-like illness, initiated by exposure to ionizing radiation. This view is supported by the nitric oxide/peroxynitrite (NO/ONOO-) cycle mechanism, the putative etiologic mechanism for CFS and related illnesses.

Ionizing radiation may initiate illness by increasing nitric oxide levels via increased activity of the transcription factor NF-kappaB and consequent increased synthesis of the inducible nitric oxide synthase. Two types of components of the nitric oxide/peroxynitrite cycle have been studied in post-radiation syndrome patients and shown to be elevated.

The symptoms and signs of post-radiation syndrome and its chronicity are similar or identical to those of chronic fatigue syndrome and can be explained as being a consequence of nitric oxide/peroxynitrite cycle etiology. While the data available to test this view are limited, it provides for the first time a comprehensive explanation for post-radiation syndrome.

 

Source: Pall ML. Post-radiation syndrome as a NO/ONOO- cycle, chronic fatigue syndrome-like disease. Med Hypotheses. 2008 Oct;71(4):537-41. doi: 10.1016/j.mehy.2008.05.023. Epub 2008 Jul 29. https://www.ncbi.nlm.nih.gov/pubmed/18667279

 

Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome

Abstract:

In addition to the debilitating fatigue, the majority of patients with chronic fatigue syndrome (CFS) experience chronic widespread pain. These pain complaints show the greatest overlap between CFS and fibromyalgia (FM). Although the literature provides evidence for central sensitization as cause for the musculoskeletal pain in FM, in CFS this evidence is currently lacking, despite the observed similarities in both diseases. The knowledge concerning the physiological mechanism of central sensitization, the pathophysiology and the pain processing in FM, and the knowledge on the pathophysiology of CFS lead to the hypothesis that central sensitization is also responsible for the sustaining pain complaints in CFS.

This hypothesis is based on the hyperalgesia and allodynia reported in CFS, on the elevated concentrations of nitric oxide presented in the blood of CFS patients, on the typical personality styles seen in CFS and on the brain abnormalities shown on brain images. To examine the present hypothesis more research is required. Further investigations could use similar protocols to those already used in studies on pain in FM like, for example, studies on temporal summation, spatial summation, the role of psychosocial aspects in chronic pain, etc.

 

Source: Meeus M, Nijs J. Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome. Clin Rheumatol. 2007 Apr;26(4):465-73. Epub 2006 Nov 18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1820749/ (Full article)

 

Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and complementary therapy to aerobic exercise

Abstract:

Increased shear stress to the endothelium increases activity of endothelial nitric oxide synthase (eNOS) with subsequent release of small quantities (nMol) of nitric oxide (NO) into the circulation. It occurs during moderate aerobic exercise mostly as a result of laminar shear stress and with whole body, periodic acceleration as a result of pulsatile shear stress. The latter is administered by means of a new, non-invasive, passive exercise device.

Moderate exercise has long been known to alleviate the symptoms of fibromyalgia and chronic fatigue syndrome and in the current study, whole body, periodic acceleration did as well. Since NO through action of eNOS has potent anti-inflammatory properties mainly by suppressing nuclear factor kappabeta activity, it is hypothesized that both diseases have chronic inflammation as their basis. Whole body periodic acceleration can be applied separately or supplementary to aerobic exercise in the treatment of fibromyalgia and chronic fatigue syndrome.

 

Source: Sackner MA, Gummels EM, Adams JA. Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and complementary therapy to aerobic exercise. Med Hypotheses. 2004;63(1):118-23. http://www.ncbi.nlm.nih.gov/pubmed/15193362

 

Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response

Abstract:

The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations.

First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients.

Second, the activation of the protein kinase R enzyme, a characteristic feature in at least subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasodilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension.

Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.

 

Source: Nijs J, De Meirleir K, Meeus M, McGregor NR, Englebienne P. Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Med Hypotheses. 2004;62(5):759-65. http://www.ncbi.nlm.nih.gov/pubmed/15082102