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Oxidative stress and antioxidative parameters and metal ion content in patients with fibromyalgia syndrome: Implications in the pathogenesis of disease
Abstract
Fibromyalgia syndrome (FMS) is characterised by diffuse muscle pain, poor sleep and unrelenting fatigue. Individuals with FMS may also experience headaches, anxiety, depression, poor memory, numbness and tingling in the extremities, cold hands and feet, irritable bowel syndrome and lowered immune function. FMS is a common chronic pain syndrome of unknown etiology and limited treatment options. Previous studies have reported oxidative stress in FMS patients, but the results were inconsistent. Oxidative stress and nitric oxide is involved in FMS pathophysiology, however, it is still not clear whether oxidative stress abnormalities are the cause of FMS. There are several studies indicating oxidative stress in patients with FMS. Oxidant (Malondialdehyde) and antioxidant (Superoxide dismutase) balances were found to be changed in FMS patients. Furthermore, increased free radical levels may be responsible for the development of FMS and free radical-mediated oxidative stress including inflammatory cytokines may also play important roles in its pathogenesis. Moreover, oxidative stress is supposed to be increased in patients with FMS which is related to the severity of FMS symptoms. Therefore, it is important to understand whether the oxidative stress parameters are involved in FMS and what is the relationship between these and antioxidants in FMS patients. In this review we will elucidate the importance of oxidative stress and antioxidants and its possible relationship with FMS. Moreover, as metal toxicity is also reported to be involved in the pathogenesis of FMS, therefore we will also try to establish the role of toxic metals in the pathogenesis of FMS.
... These toxic molecules become highly reactive in their formation because of their altered number of unmatched valence electrons. These RNS are suggested to play important roles in rheumatologic conditions like rheumatoid arthritis, ankylosing spondylitis, and chronic fatigue syndrome (CFS) (4,5). There is little information on oxidative stress in FM, but the level of malondialdehyde is higher and superoxide dismutase is lower than that of the control (6,7). ...
... Recent hypotheses of FM etiology have highlighted inflammatory disorders accompanied by changes in redox imbalance (5,26). Studies have shown that subjects with FM show increased plasma levels of TBARS compared to healthy individuals (31). ...
... In this study, women with FM presented higher plasma level of TBARS compared to resting healthy individuals, characterized by the presence of redox imbalance, which may lead to an inflammatory profile in the FM subjects (37). The literature points out that balanced oxidative stress and chronic systemic low-grade inflammation are potent mediators of homeostasis (5). Exercise seems to have the capacity to transiently provoke a response in both biological systems (26). ...
The objective of this study was to investigate the effect of whole body vibration (WBV) exercise on oxidative stress markers in a group of women with fibromyalgia (FM) compared to a group of healthy women (CT). Twenty-one women diagnosed with FM and 21 age- and weight-matched healthy women were enrolled the study. Plasma oxidative stress markers (primary outcomes) were evaluated at rest and after WBV, and included thiobarbituric acid reactive substances (TBARS), iron reduction capacity (FRAP), superoxide dismutase antioxidant enzymes activity (SOD), and catalase (CAT). At rest, the FM group had higher TBARS (P<0.001) and FRAP (P<0.001), and lower CAT (P=0.005) compared to the CT. In the CT group, the WBV had no effect on TBARS (P=0.559) and FRAP (P=0.926), whereas it increased both SOD (P<0.001) and CAT (P<0.001). In the FM group, the WBV reduced TBARS (p <0.001), FRAP (P<0.001), and CAT (P=0.005), while it increased SOD (P=0.019). There was an interaction effect (moments vs groups) in the TBARS (effect size=1.34), FRAP (effect size=0.93), CAT (effect size=1.45), and SOD (effect size=1.44) (P<0.001). A single trial of WBV exercise improved all oxidant and antioxidant parameters towards a greater adaptation to the stress response in FM women.
... In particular, it is not clear whether the disease is caused by oxidative stress. 97 Enhanced oxidative stress mediated by free radicals is however evident in FMS and leads to increased cytokine expression. There is much evidence that suggests that increased oxidative stress leads to increased severity of FMS symptoms. ...
... There is much evidence that suggests that increased oxidative stress leads to increased severity of FMS symptoms. 81,97 In particular, a positive correlation has been observed between FIQ and increased lipid peroxidation. 81 Malondialdehyde is a toxic metabolite of lipid peroxidation, and significantly increased levels of this metabolite have repeatedly been found in patients with FMS. ...
... Ambroxol for fibromyalgia oxidative, 24,81,97 or muscular factors 84,132,134 and/or central sensitization. 42,175,176 On the basis of this hypothesis, fibromyalgia treatment with ambroxol should be systematically investigated, since this compound is the only treatment option used thus far that has the potential to address not just individual but all of the aforementioned aspects of pain. ...
Fibromyalgia appears to present in subgroups concerning biological pain induction with primarily inflammatory, neuropathic/neurodegenerative, sympathetic, oxidative, nitrosative or muscular factors and/or central sensitization. Recent research also discussed a glial activation or interrupted dopaminergic neurotransmission as well as increased skin mast cells and mitochondrial dysfunctions. Therapy is difficult and the treatment options used so far mostly just have the potential to address only one of these aspects. As Ambroxol addresses all of them in a single substance and furthermore also reduces visceral hypersensitivity, in fibromyalgia existing as irritable bowel syndrome or chronic bladder pain, it should be systematically investigated for this purpose. Encouraged by first clinical observations of two working groups using topical or oral ambroxol for fibromyalgia treatments the present paper outlines the scientific argumentation for this approach by looking at each of the above mentioned aspects of this complex disease and summarizes putative modes of action of ambroxol. Nevertheless at this point the evidence basis for ambroxol is currently not strong enough for clinical recommendation.
... Moreover, degeneration and regeneration of NMJ architecture in skeletal muscle fibres have also been reported [21]. Oxidative stress and nitric oxide are involved in NMDs, especially FMS pathophysiology [22]. It is, however, still not clear whether oxidative stress abnormalities are the causes of FMS. ...
... It is, however, still not clear whether oxidative stress abnormalities are the causes of FMS. The balance between oxidant (malondialdehyde) and antioxidant (superoxide dismutase) was found to be disturbed in FMS patients [22]. Furthermore, increased free radical levels may be responsible for the development of FMS and free radical-mediated oxidative stress including inflammatory cytokines may also play important roles in its pathogenesis [22,23]. ...
... The balance between oxidant (malondialdehyde) and antioxidant (superoxide dismutase) was found to be disturbed in FMS patients [22]. Furthermore, increased free radical levels may be responsible for the development of FMS and free radical-mediated oxidative stress including inflammatory cytokines may also play important roles in its pathogenesis [22,23]. The literature mentioned above undoubtedly proves a connection between stress and NMDs, but the findings are few and far apart. ...
Aging is associated with a progressive loss of muscle strength and mass, and a decline in neurophysiologic functions. Understanding aging induced neuromuscular junction (NMJ) dysfunction is very crucial to understand musculoskeletal impairment during aging. Morphological and physiological changes results in a remodelling of the motor unit and in a decline of the number of motor neurons muscle fibre. These alterations lead to excitation–contraction uncoupling, and a loss of communication between the neuromuscular system, causing a decline in skeletal muscle strength and muscle mass. Understanding the molecular basis of NMJ dysfunction is essential in search for new treatment options. Besides structural and molecular studies, search for animal models to establish connection between brain and muscle are needed. Among various factors it has been observed that stress is one of the leading causes of neuromuscular disorders. In the present review, we aim to explore the dynamic relationship between stress and neuromuscular disorders which gets aggravated by aging, which will help us gain new insights in its cure and by aiding in improved symptoms, increased mobility and lengthened life.
... The role of mitochondrial oxidative stress in FM pathogenesis has been widely discussed [6,9]. Previous studies have shown that patients with FM have high plasma levels of TBARS [4,5] and low plasma levels of SOD and CAT [7][8][9], indicating a pro-oxidative state. Among the complementary strategies for treating FM, physical exercise is recommended. ...
... It has been extensively discussed [6,9] how mitochondrial oxidative stress contributes to FM development. A pro-oxidative state is evident in individuals with FM, as demonstrated by their high plasma levels of TBARS [4,5] and low plasma levels of SOD and CAT [7][8][9]. Exercise is one of the additional methods advised for treating FM. However, it is important to note that depending on the level of physical exertion, gender, age, and physical condition, improper exercise might have a harmful effect on the body. ...
(1) Background: Mitochondrial dysfunction and redox imbalance seem to be involved in fibromyalgia (FM) pathogenesis. The results of our previous studies suggest that whole-body vibration training (WBVT) would improve redox status markers, increase blood irisin levels, and ameliorate the body composition of women with FM. (2) Objective: The current study aimed to investigate WBVT on oxidative stress markers, plasma irisin levels, and body composition in women with FM. (3) Methods: Forty women with FM were randomized into WBVT or untrained (UN) groups. Before and after 6 weeks of WBVT, body composition was assessed by dual-energy radiological absorptiometry (DXA), and inflammatory marker activities were measured by enzymatic assay. (4) Results: Body composition, blood irisin levels, and oxidative stress markers were similar between UN and WBVT groups before the intervention. After 6 weeks of intervention, the WBVT group presented higher irisin levels (WBVT: 316.98 ± 109.24 mg·dL³, WBVT: 477.61 ± 267.92 mg·dL³, p = 0.01) and lower TBARS levels (UN: 0.39 ± 0.02 nmol MDA/mg protein, WBVT: 0.24 ± 0.06 nmol MDA/mg protein, p = 0.001) and visceral adipose tissue mass (UN: 1.37 ± 0.49 kg, WBVT: 0.69 ± 0.54 kg, p = 0.001) compared to the UN group. (5) Conclusions: Six weeks of WBVT improves blood redox status markers, increases irisin levels, and reduces visceral adipose tissue mass, favoring less cell damage and more outstanding oxidative balance in women with FM.
... Although females are shown to be more prone to developing FM, the predominant population in our study consisted of males. Also, fibromyalgia was relatively more frequent among the youngest population (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), as opposed to the usual age of presentation in the general population [15]. Increased prevalence in males can be explained by the constant stress of bread-earning responsibility for their families, and certainly a communication gap between healthcare providers and FM-diagnosed males [21]. ...
... The latest medical literature suggests that FM-related inflammation is caused by plasma-derived factors cytokines, reactive oxygen species, and lipid mediators, thus opening doors to effective therapeutic approaches [28]. Also, antioxidants, as treatment options are encouraged, as FMS leads to disbalances between malondialdehyde, an oxidant, and superoxide dismutase, an antioxidant [29]. ...
Background
Fibromyalgia syndrome (FMS) is an umbrella term for chronic pain syndrome, associated with tenderness, fatigue, reduced pain thresholds, and paresthesia in the limbs. The field of medicine places doctors in constant work-related stress, sleep deprivation, and depression, thus increasing their vulnerability to developing FMS. This study aims to evaluate the prevalence and severity of FM (fibromyalgia) among physicians in a tertiary care hospital setting.
Methods
The cross-sectional study was performed at the Pakistan Institute of Medical Sciences, Islamabad, Pakistan, from December 2019 to December 2020.243 physicians of either gender, and from all the departments being house officers, medical officers, and post-graduate trainees were included & divided into 3 age groups from 20 to more than 45 years. Widespread Pain Index (WPI) equal to or more than 7 and Symptom Severity Score (SSS) equal to or more than 5 OR WPI = 3 to 6 and SSS equal to or more than 9 were required, according to the modified American College of Rheumatology preliminary diagnostic criteria 2016 for fibromyalgia diagnosis. Data was analyzed using SPSS 25.
Results
Among a total of 243 participants, FMS was diagnosed in 69 (28.40%) individuals. The predominant FMS population was the youngest age group 20–35 (56 = 81.16%). Increased BMI, increasing pain score category, gender, and comorbidities are significantly associated with FMS (p ≤ 0.05). Whereas, advancing age is insignificantly linked with FMS (p > 0.05).
Conclusions
The prevalence of fibromyalgia was found to be high among doctors working in stressful hospital settings, particularly among the youngest ones.
... Lipid peroxidation causes membrane rupture and the release of cellular materials to extracellular space. [3] In normal circumstances, the oxidant and antioxidant status of the cellular and extracellular space are in balance. Any disruption of this balance will direct it towards the oxidant or antioxidant side. ...
Objectives: This study aims to reveal the relationship between serum total antioxidant status (TAS), clinical parameters, and nutrition (dietary total antioxidant capacity [TAC]) in patients with fibromyalgia.
Patients and methods: This cross-sectional study was conducted with a total of 60 female participants (mean age: 44.7±9.7 years; range, 18 to 50 years) at Gaziler Physical Medicine and Rehabilitation Hospital between July 2020 and February 2021. Thirty female patients with fibromyalgia were compared with 30 age-, sex-, and body mass index-matched healthy individuals. The short-form McGill Pain Questionnaire, Fibromyalgia Impact Questionnaire (FIQ), and Pittsburg Sleep Quality Index were used. Total antioxidant status, total oxidant status (TOS), and oxidative stress index (OSI) were measured. Dietary TAC was calculated using the ferric reducing ability of plasma according to a food frequency questionnaire.
Results: Total antioxidant status showed no significant difference between groups (p=0.080). Total oxidant status and OSI were significantly higher in the patient group (p<0.001 and p=0.005, respectively). The mean dietary TAC was 16.5±6.5 in the patient group and 17.2±6.2 in the control group, and it was similar between groups (p=0.492). Pittsburg Sleep Quality Index global score was significantly higher in the patient group than in the control group (p<0.001). Dietary TAC showed a moderate positive correlation with serum TAS in both groups (r=0.373, p=0.042 for the patient group, and r=0.380, p=0.038 for the control group). In the patient group, TOS and OSI showed a moderate positive correlation with FIQ total scores (r=0.420, p=0.021 and r=0.450, p=0.013, respectively). The mean polyunsaturated fatty acid and omega-6 intake of the patient group was significantly lower than the control group (p=0.025 for both). Dietary antioxidant intake from vegetables (p=0.025), legumes/nuts (p=0.049), and meat (p<0.001) was significantly lower, whereas dietary antioxidant intake from cereal and potatoes was significantly higher in the patient group compared to the control group (p=0.028).
Conclusion: The results indicate that oxidative stress can be reduced by increasing dietary antioxidant intake in fibromyalgia.
... PTSD has also been frequently related to several further co-morbidities, such as chronic fatigue syndrome (CFS) [261][262][263], fibromyalgia [264][265][266][267][268], irritable bowel syndrome (IBS) [269], and rheumatoid arthritis [270], which all share a very similar underlying neuroendocrinological profile to PTSD (e.g., hypocortisolism, blunted diurnal GC rhythm and HPA axis reactivity) [271][272][273][274][275] and have all been repeatedly associated with increased OXS [276][277][278][279][280][281][282]. ...
Traumatic stress may chronically affect master homeostatic systems at the crossroads of peripheral and central susceptibility pathways and lead to the biological embedment of trauma-related allostatic trajectories through neurobiological alterations even decades later. Lately, there has been an exponential knowledge growth concerning the effect of traumatic stress on oxidative components and redox-state homeostasis. This extensive review encompasses a detailed description of the oxidative cascade components along with their physiological and pathophysiological functions and a systematic presentation of both preclinical and clinical, genetic and epigenetic human findings on trauma-related oxidative stress (OXS), followed by a substantial synthesis of the involved oxidative cascades into specific and functional, trauma-related pathways. The bulk of the evidence suggests an imbalance of pro-/anti-oxidative mechanisms under conditions of traumatic stress, respectively leading to a systemic oxidative dysregulation accompanied by toxic oxidation byproducts. Yet, there is substantial heterogeneity in findings probably relative to confounding, trauma-related parameters, as well as to the equivocal directionality of not only the involved oxi-dative mechanisms but other homeostatic ones. Accordingly, we also discuss the trauma-related OXS findings within the broader spectrum of systemic interactions with other major influencing systems, such as inflammation, the hypothalamic-pituitary-adrenal axis, and the circadian system. We intend to demonstrate the inherent complexity of all the systems involved, but also put forth associated caveats in the implementation and interpretation of OXS findings in trauma-related research and promote their comprehension within a broader context.
... Furthermore, increased free radical levels may be responsible for the development of FMS, and free radical-mediated oxidative stress, including inflammatory cytokines, may also play important roles in its pathogenesis. 34 To the best of our knowledge, the current study is the first of its kind conducted in the Pakistani population. It has made significant observations that can be further explored in well-designed, longitudinal, multi-centre studies. ...
Objective:
To assess the prevalence and severity of fibromyalgia in hospital-visiting patients.
Methods:
The cross-sectional study was conducted at the Pakistan Institute of Medical Sciences, Islamabad, Pakistan, from July, 2018, to January, 2019, and comprised patients aged 18-75 years of either gender. Demographic information, comorbidities and previous medications were recorded for each patient. The modified American College of Rheumatology preliminary diagnostic criteria 2010-11 for fibromyalgia diagnosis. If diagnosed, the fibromyalgia impact questionnaire was administered to assess its severity. Data was analysed using SPSS 25.
Results:
Of the 750 hospital-visiting patients, fibromyalgia was diagnosed in 250(33.3%); 190(76%) of them being females (p<0.0001). Comorbidities, age and increased elevated body mass index were significantly associated with fibromyalgia. Severity was not influenced by comorbidities, marital status, education or economic status (p>0.05). Menarche at a later age and menstrual irregularity were associated with fibromyalgia severity (p<0.05).
Conclusions:
The hospital-based prevalence of fibromyalgia was found to be high, especially among females.
... Glycolytic enzymes such as PGK1 and GAPDH are usually found in the cytoplasm and released into the general circulation during pathological states that correlate with cell damage or apoptosis [29]. In this context, it may be hypothesized that conditions of oxidative stress involved in myalgia may increase the need of PGK1 and GAPDH [31]. ...
In the last years, several attempts have been made to study specific biological markers of temporomandibular disorders (TMD). So far, no laboratory tests have been appropriately validated for the diagnosis and prognosis of these disorders. This study aimed to investigate the proteomic profile of the whole stimulated saliva of TMD myalgia patients in order to evaluate potential diagnostic and/or prognostic salivary candidate proteins which could be useful for the management of TMD. Twenty patients diagnosed with TMD myalgia according to the validated Diagnostic Criteria for TMD (DC/TMD) and 20 matched healthy pain-free controls were enrolled. Saliva samples were collected in the morning. Comparative proteomic analysis was performed with two-dimensional gel electrophoresis followed by identification with liquid chromatography–tandem mass spectrometry. Statistical analysis of the quantitative proteomics data revealed that 20 proteins were significantly altered in patients compared to controls. Among these proteins, 12 showed significantly increased levels, and 8 showed significantly decreased levels in patients with TMD myalgia compared to controls. The identified proteins are involved in metabolic processes, immune response, and stress response. This proteomic study shows that the salivary protein profile can discriminate patients with TMD myalgia from healthy subjects, but the protein signature has no correlation with the clinical features of TMD myalgia. Additional studies are needed to validate our observations in additional sample sets and to continue assessing the utility of saliva as a suitable sample for studying processes related to TMD myalgia.
... Oxidative stress (OS) and Co Q play a role in neuro-musculoskeletal conditions such as FM so the providing of antioxidants kept tissues faraway from unpleasant effects of OS (39)(40)(41)(42) . In Egyptian study by Soliman et al showed that the level of (OS) increased with decreased of antioxidant capacity significantly these findings in concomitant with the present study in premenopausal age (43) . ...
The objective of this study is to evaluate the level of parathyroid hormone, Co enzyme Q and total antioxidant status in serum’s women with fibromyalgia syndrome firstly, then to demonstrate if these biochemical markers affected by age and obesity.
This study was performed at Rheumatology and Rehabilitation Consultation Unit in Baghdad Teaching Hospital. Venous blood sample were drawn from (59) female with FMS and (30) control (without FMS). The serum was obtained after on standing in order to coagulate then centrifuged. The mean age± SD of FMS group was (42.22±15.34) years and for control was (40.7±18.22) years. Those participants were subdivided into four different groups according to menopausal status and body mass index to estimate three biochemical markers in their serum. The assessment of serum both PTH and Co enzyme Q were done by enzyme linked immune sorbent assay (ELISA) while total antioxidant status (TAS) determination was done colorimetric ally. Statistical analysis was calculated by SPSS program version 24. Independent samples T-test for different group of patients Pearson correlation between serum’s biomarkers within different groups; P values < 0.05 means significant.
The results record that serum’s PTH showed increasing significantly at same time of decreasing Co Q (P value 0.05) in FMS comparing with control group. About the age; PTH serum level appear insignificant increased but Co Q & TAS were decreased (P value >0.05& P value< 0.05) respectively in post menopause comparing with pre menopause. For estimating serum’s biomarkers related with body mass index (BMI) as a sign of obesity. Serum PTH level record significant raise in obese group P value0.05) in the same time TAS record a significant decrease in obese group P value= 0.00.
In pre menopause (FMS and control): Serum TAS level correlate negatively and significantly with PTH (P value= 0.034). For age>55; PTH in both FMS& control show critical significant correlation P value=0.05. In pre and post menopause FMS show significant independent t-test belong to TAS (P value= 0.004). In obese group PTH correlate Co Q of 2530 significantly P value=0.027 and P value=0.029. T test show significant in PTH and TAS between obese and non-obese.
In conclusion the obesity and menopause play an imperative role in the etiology of FMS relative with serum’s biomarkers (PTH, Co Q and TAS).
... A concomitant treatment of melatonin and folic acid was able to reduce the increased pain sensibility and the depression-like behaviour with more efficacy than them single administration. Increasing evidence suggests that enhanced oxidative stress and nitric oxide are involved in the fibromyalgia pathophysiology and increase the severity of the symptoms [53,54]. We are in line with literature [55,56]; our data also underlines that the oxidative and nitrosative stress induces neurogenic inflammation which is responsible for the perpetuation of pain [16]. ...
Background:
Fibromyalgia is a chronic condition characterized by increased sensory perception of pain, neuropathic/neurodegenerative modifications, oxidative, and nitrosative stress. An appropriate therapy is hard to find, and the currently used treatments are able to target only one of these aspects.
Methods:
The aim of this study is to investigate the beneficial effects of melatonin plus folic acid administration in a rat model of reserpine-induced fibromyalgia. Sprague-Dawley male rats were injected with 1 mg/kg of reserpine for three consecutive days and later administered with melatonin, folic acid, or both for twenty-one days.
Results:
Administration of reserpine led to a significant decrease in the nociceptive threshold as well as a significant increase in depressive-like symptoms. These behavioral changes were accompanied by increased oxidative and nitrosative stress. Lipid peroxidation was significantly increased, as well as nitrotyrosine and PARP expression, while superoxide dismutase, nonprotein thiols, and catalase were significantly decreased. Endogenously produced oxidants species are responsible for mast cell infiltration, increased expression pro-inflammatory mediators, and microglia activation.
Conclusion:
Melatonin plus acid folic administration is able to ameliorate the behavioral defects, oxidative and nitrosative stress, mast cell infiltration, inflammatory mediators overexpression, and microglia activation induced by reserpine injection with more efficacy than their separate administration.
... In diseases associated with the central nervous system, the structure of the blood-brain barrier is frequently impaired; consequently, lymphocytes are able to enter the brain parenchyma through the blood-brain barrier (4). These immune cells may initiate various physiopathological reactions in the brain, and the activation of certain signaling pathways is able to mediate the elimination of various infectious agents (5). Metabolic disorders, including type II diabetes and obesity, are the principal factors associated with metabolic inflammation (6). ...
High fat diet (HFD) is a risk factor for various diseases in humans and animals. Metabolic disease‑induced brain injury is becoming an increasingly popular research topic. Carnosic acid (CA) is a phenolic diterpene synthesized by plants belonging to the Lamiaceae family, which exhibits multiple biological activities. In the present study, a mouse model of HFD‑induced metabolic syndrome was generated. The body weight, liver weight, daily food intake, daily caloric intake, serum TG, serum TC, serum insulin and serum glucose of animals treated with CA were recorded. Additionally, the gene and protein expression levels of inflammatory cytokines, NF‑κB signaling componnts, and caspase‑3 were evaluated in the various CA treatment groups via immunohistochemical analysis, western blotting, reverse transcription‑quantitative PCR. CA treatment significantly decreased HFD‑induced metabolic syndrome by decreasing the serum levels of triglycerides, total cholesterol, insulin and glucose. Furthermore, CA served a protective role against brain injury by inhibiting the inflammatory response. CA significantly decreased the protein expression levels of various pro‑inflammatory cytokines in serum and brain tissues, including interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α, regulated by the NF‑κB signaling pathway. In addition, CA was revealed to promote the expression levels of anti‑apoptotic Bcl‑2, and to decrease the expression levels of pro‑apoptotic Bax and matrix metallopeptidase 9. The present results suggested that CA was able to alleviate brain injury by modulating the inflammatory response and the apoptotic pathway. Administration of CA may represent a novel therapeutic strategy to treat metabolic disease‑induced brain injury in the future.
... The antioxidant enzyme activities were presumed to increase in response to the increased oxidative stress activity. [32][33][34][35] This might be due to the activation of the nuclear factor (erythroid-derived-2)-like 2 transcription factor, which is activated in oxidative stress conditions and induces antioxidant response elements. [36][37][38] Oxidative markers were not correlated with disease severity, but some parameters (SOD-balance) were associated with audiological complaints. ...
Aim: Central sensitization-related neuroaudiological symptoms are frequently
seen in patients with fi bromyalgia syndrome (FMS). This study aimed to
evaluate the audiological signs and symptoms in patients with FMS and explore
their relationship with oxidative stress markers. Methods: This prospective
controlled cross-sectional study compared the serum myeloperoxidase,
superoxide dismutase, glutathione peroxidase (GPx), nitric oxide (NO), and
malondialdehyde (MDA) concentrations in 44 patients with FMS diagnosed
according to the 2010 American College of Rheumatology criteria and 44
healthy volunteers. FMS severity was assessed using the visual analog scale
and Fibromyalgia Impact Questionnaire. An audiological assessment including
vocalizations, vertigo, balance problems, and hearing problems was done
to all participants. Results: The two groups were of similar age (P = 0.24),
gender (P = 0.40), and weight distribution (P = 0.6). Vertigo, tinnitus, hearing,
and balance complaints (P = 0.01/P = 0.00/P = 0.00/P = 0.01) were signifi cantly
higher in the FMS group. All subunits and total scores of dizziness handicap
inventory were signifi cantly higher (P = 0.00/P = 0.00/P = 0.01/P = 0.01) in
the FMS group. An antioxidant GPx and oxidant parameters such as NO and
MDA were found to be signifi cantly higher (P = 0.00/P = 0.01/P = 0.02).
The hearing assessments at frequencies between 250 and 12,000 Hz showed a
signifi cant difference between the two groups (high hearing frequencies in the
FMS group) in audiometry. No signifi cant difference was found between the two
groups in terms of the presence of stabilo-acoustic refl ex, intraaural pressure, and
compliance (P = 0.18/P = 0.33/P = 0.41) in tympanogram. Conclusions: Patients
with FMS have high levels of oxidative stress markers (GPx, NO, and MDA),
highly frequent audiological symptoms with high hearing frequencies in
audiometry, independent of disease severity.
... There are studies indicating an imbalance between oxidants and antioxidants in patients with FMS. [7][8][9][10] The results are controversial. To the best of our knowledge, no report related to thiol/disulphide homeostasis in FMS has been published. ...
Objectives:
This study aims to investigate dynamic thiol/disulphide homeostasis in patients with fibromyalgia syndrome (FMS).
Patients and methods:
Fifty female patients with FMS (mean age 40.5±7.2 years; range 21 to 55 years) and 40 healthy female controls (mean age 39±9.4 years, range 22 to 55 years) were included in the study. Pain visual analog scale, tender points, Fibromyalgia Impact Questionnaire, and Beck Depression Inventory were evaluated. Age, body mass index (BMI), and symptom durations were also recorded. Native thiol, disulphide and total thiol levels were measured with a novel automated method.
Results:
Serum disulphide levels were 14.7±3.4 μmol/L and 22.2±3.6 μmol/L in the FMS and control groups, respectively (p<0.001). Native thiol levels were 452.1±33.8 μmol/L and 433.5±37.6 μmol/L in the FMS and control groups, (p=0.015), while total thiol levels were 481.7±35.6 μmol/L and 477.5±38.9 μmol/L in the FMS and control groups, respectively (p=0.593). In the FMS group, disulphide/native thiol percent ratios and disulphide/ total thiol percent ratios were statistically significantly lower and native/total thiol percent ratios were statistically significantly higher than those of the control group. There were no correlations between serum thiol/disulphide profiles and pain scores & clinical variables in patients with FMS.
Conclusion:
Because of the decreased disulphide and increased native thiol levels, the thiol/disulphide balance has shifted to the reductive side. This metabolic disturbance may have a role in the pathogenesis of FMS.
Background
Fibromyalgia patients who are exposed to extreme oxidative stress may face more severe clinical features or oxidative stress may be increased by the severity of the disease.AimThe purpose of these investigation were to determine serum paraoxonase activities (PON-1) and nitric oxide (NO) activities and malondialdehyde (MDA) level in fibromyalgia and whether there were any associations between these enzymes activities, MDA level, and clinical parameters.Methods
The study groups were consisted of 30 primer fibromyalgia patients and 30 healthy subjects. Clinical findings, pain severity, functional disability, general health status, anxiety, and depression assessed, and serum PON-1 activity, MDA, and NO levels were measured.ResultsThe primer fibromyalgia group had significantly higher MDA, low density lipoprotein-cholesterol (LDL-C), and decreased PON-1 activity, NO, and high density lipoprotein-cholesterol (HDL-C) with respect to controls. The paraoxonase activity was negatively correlated with MDA, LDL-C, Visual Analog Scale (VAS), Fibromyalgia Impact Questionnaire score (FIQ score), tender point score, age, and BDI score, while positively correlated with NO and HDL-C. MDA level was positively correlated with VAS, FIQ score, tender point score, age, and negatively correlated with NO level.Conclusion
These results suggest that FMS patients have an alteration in levels of MDA, NO, and PON-1 activities. We think that impaired oxidant/antioxidant status may affect the symptoms of the disease. Also, they may be of importance in the complex physiopathologic mechanism behind the development of FMS.
The person who is pregnant or preparing for pregnancy in the setting of chronic pain is likely to have an especially keen interest in management approaches beyond the usual biomedical model, which tends to focus on symptom management without addressing root causes. Providers and patients also have heightened concerns about the limited efficacy and adverse effects of pharmaceutical management of pain before and during pregnancy. Research increasingly supports an association between diet and chronic pain. Improvements in nutrition will not only facilitate the management of chronic pain but also greatly enhance childbearing outcomes. Persons approaching pregnancy usually have a heightened motivation to make health-enhancing behavioral changes. Chronic pain conditions in the person who is pregnant or preparing for pregnancy present a valuable opportunity to identify and treat underlying causes to enhance long-term health and well-being for the individual and their offspring, impacting the health of the next generation.This chapter utilizes a functional medicine framework in describing the role of diet and nutritional supplements that are safe and beneficial in those living with chronic pain who are preparing for pregnancy or pregnant. Functional medicine provides a framework for understanding and addressing the complex and interrelated factors that create optimal health. Utilizing a systems biology approach, functional medicine recognizes and addresses eight core systems that can be imbalanced (e.g., defense and repair systems, energy production, biotransformation and elimination, transport, communication, structural integrity, and assimilation). Functional medicine focuses on evaluating these systems and finding within them the root cause(s) for illness relying on nutrition, supplements, and lifestyle measures to address and resolve those underlying drivers of imbalance. This chapter will support the healthcare provider to develop an evidence-based plan utilizing diet therapy, functional foods, and nutraceuticals to effectively improve symptoms, quality of life, and comorbidities in people living with chronic pain while simultaneously optimizing fertility and pregnancy outcomes.KeywordsChronic painMicrobiomePregnancyDietNutritionDiet inflammatory indexFunctional medicineFunctional foodsOmega-3Vitamin D
Fibromyalgia syndrome (FMS) and chronic widespread musculoskeletal pain (CMP) are diffuse suffering syndromes that interfere with normal activities. Controversy exists over the role of vitamin D in the treatment of these diseases. We carried out a systematic literature review of randomized controlled trials (RCT) to establish whether vitamin D (25OHD) deficiency is more prevalent in CMP patients and to assess the effects of vitamin D supplementation in pain management in these individuals. We searched PubMed, Physiotherapy Evidence Database (PEDro), and the Cochrane Central Register of Controlled Trials (CENTRAL) for RCTs published in English from 1 January 1990 to 10 July 2022. A total of 434 studies were accessed, of which 14 satisfied the eligibility criteria. In our review three studies, of which two had the best-quality evidence, a correlation between diffuse muscle pain and 25OHD deficiency was confirmed. Six studies, of which four had the best-quality evidence, demonstrated that appropriate supplementation may have beneficial effects in patients with established blood 25OHD deficiency. Eight studies, of which six had the best-quality evidence, demonstrated that 25OHD supplementation results in pain reduction. Our results suggest a possible role of vitamin D supplementation in alleviating the pain associated with FMS and CMP, especially in vitamin D-deficient individuals.
Keywords: vitamin D; fibromyalgia; widespread pain; hypovitaminosis; systematic review
IntroductionThe multifaceted clinical presentation of fibromyalgia (FM) supports the modern understanding of the disorder as a more global condition than one simply affecting pain sensation. The main pharmacologic therapies used clinically include anti-epileptics and anti-depressants. Conservative treatment options include exercise, myofascial release, psychotherapy, and nutrient supplementation.Methods
Narrative review.ResultsNutrient supplementation is a broadly investigated treatment modality as numerous deficiencies have been linked to FM. Additionally, a proposed link between gut microbiome patterns and chronic pain syndromes has led to studies investigating probiotics as a possible treatment. Despite positive results, much of the current evidence regarding this topic is of poor quality, with variable study designs, limited sample sizes, and lack of control groups.Conclusions
The etiology of FM is complex, and has shown to be multi-factorial with genetics and environmental exposures lending influence into its development. Preliminary results are promising, however, much of the existing evidence regarding diet supplementation is of poor quality. Further, more robust studies are needed to fully elucidate the potential of this alternative therapeutic option.
To ensure that the supplements recommended with the Mind-Body Wellness Program do not add to stress through contraindications, the contraindications are described. For example, alpha-lipoic acid may lower resting blood pressure, contraindicating it for patients with low resting pressure. The recommended supplements and lifestyles form this kernel of a Wellness Program. The weight of scientifically rigorous and statistically significant evidence behind this program is brought to bear in this chapter as it subserves functional medicine as well as clinical medicine. For example, additions to this kernel that help to tailor the program to specific conditions are presented. For example, by adding cannabidiol, the program is customized for pain management (including fibromyalgia) or anxiety. Neurofeedback is also introduced as another means of treating P&S imbalance, as an adjunct to the program.
Depression and pain comorbidity represent a neuropsychiatric condition with substantial socioeconomic impact to society. The commonly used antidepressants and analgesics to treat this comorbidity have shown restricted clinical efficacy. In this way, the aim of this study was to investigate the behavioral, biochemical and neurochemical effects of a p,p’-methoxyl-diphenyl diselenide (OMePhSe)2 supplemented diet on pain-depression dyad induced by reserpine in rats. Adult Wistar rats were fed with 10 mg (MeOPhSe)2 per kg of rat chow supplemented diet for 30 days. Pain-depression dyad was induced by daily subcutaneous reserpine injection (0.5 mg/kg for three consecutive days) from 22 to 24 day of (MeOPhSe)2 supplementation. The results showed that the reserpine injected rats had behavior phenotypes typical of depression-pain dyad and the (MeOPhSe)2-supplemented diet protected against these modifications. Furthermore, the (MeOPhSe)2 dietary supplementation was effective against the increase in the prefrontal cortical MDA levels caused by reserpine. (MeOPhSe)2-supplemented diet triggered a per se augmentation of Nrf-2 levels. The [³H] serotonin uptake, [³H] glutamate uptake and release and MAO activity were not altered in the prefrontal cortices of rats from any experimental group. Therefore, the results indicate that protective effects of a (MeOPhSe)2-supplemented diet can be mediated, at least in part, by its antioxidant property.
Fibromyalgia is a syndrome characterized by widespread pain and is commonly associated with fatigue, muscle tenderness, and headaches. The current body of knowledge regarding the pathogenesis of fibromyalgia suggests that diet has the potential to both exacerbate and diminish symptoms common to this disorder. A greater understanding of the role that oxidative stress, mineral deficiencies, and dietary excitotoxins play in the disease process has encouraged numerous therapeutic studies. Trial investigations of antioxidant therapies and structured diets emphasizing plant-based foods have produced encouraging results. However, conflicting outcomes or confounding factors continue to compromise much of the available evidence concerning nutrition and its relationship to fibromyalgia. More studies are needed to create specific clinical recommendations regarding diet and supplement use in fibromyalgia.
In the present study we examined the involvement of oxidative and antioxidative parameters in women with fibromyalgia syndrome (FMS) and also evaluated their correlation with Fibromyalgia Impact Questionnaire Revised (FIQR).
Oxidative stress was determined by measuring the levels of lipid peroxides (LPO) and protein carbonyls in plasma and antioxidative parameters like catalase, glutathione peroxidase (GPx) and glutathione reductase (GR) in blood lysate in 30 female patients satisfying the American College of Rheumatology (ACR) criteria for FMS and 30 healthy females without FMS. Clinical parameters of FMS were evaluated by FIQR.
Activity of enzymes catalase (patients, 41.0 ± 0.94; controls, 57.3 ± 1.58), GR (patients, 24.4 ± 0.77; controls, 28.1 ± 1.13) and GPx (patients, 28.2 ± 0.69; controls, 38.7 ± 0.93) were significantly lower in patients with FMS than in controls, and levels of oxidative stress parameters, LPO (patients, 3.31 ± 0.10; controls, 2.2 ± 0.06) and protein carbonyls (patients, 1.90 ± 0.08; controls, 1.32 ± 0.04) were significantly higher in patients than in controls. A significant positive correlation was found between LPO and FIQR in the patient group. Furthermore, a significant positive correlation was also found between protein carbonyls and FIQR in the patient group than in the control group.
The present results indicate that women with FMS are exposed to oxidative stress. Moreover, our results also showed that increased oxidative stress parameters are more strongly associated with severity of FMS.
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.
An estimated 10%-15% of women of reproductive age suffer from endometriosis and can be plagued with one or many forms of pain. It is no mystery that endometriosis is an extremely complex disease, with several factors leading to the predominant symptoms of infertility and pain. Although there are currently multiple options available for treating endometriosis-associated pain, none have the ability to completely relieve the symptoms. This review both highlights the current trends in treatment of endometriosis- associated pain and explores some novel options available for therapy directed towards oxidative stress, inflammation and nociceptive mechanisms of pain. A PubMed search was conducted to identify the most recent publications on the topic of pain associated with endometriosis, and further research was performed to clarify the mechanism by which current treatments target pain. Lastly, the authors include a review of pharmacological options at the forefront of endometriosis research. A more comprehensive understanding of the mechanisms behind endometriosis-associated pain will ultimately lead to more effective treatments and improved prognoses for patients.
Fibromyalgia syndrome (FMS) is a chronic disorder characterised by widespread musculoskeletal pain, troubled sleep, disturbed mood, and fatigue. Recently published reviews have demonstrated that it is influenced by various psychological aspects, and antidepressants are now considered the treatment of choice for most patients. The aim of this randomised controlled trial was to compare the effects of duloxetine and acetyl L-carnitine on pain, depression, anxiety and well-being in FMS patients.
Sixty-five female outpatients with FMS diagnosed by a rheumatologist were recruited between January 2011 and May 2012, and randomised to receive duloxetine 60 mg/day or acetyl L-carnitine 1500 mg/day (500 mg t.i.d.). Drug efficacy and side effects were assessed by the same psychiatrist at baseline, and four and 12 weeks later.
Both drugs led to a general clinical improvement, with positive effects on pain and depressive symptoms; but neither induced a significant improvement in anxiety. Both drugs had a positive effect on the physical component of the quality of life, but only duloxetine improved the psychological component.
Although they need to be confirmed by further studies, these preliminary findings confirm the efficacy of duloxetine, and suggest that acetyl L-carnitine is also efficacious in improving depressive symptoms, pain, and the quality of life of FMS patients.
Fibromyalgia syndrome (FM) is a chronic, generalised pain condition usually accompanied by several associated symptoms, such as fatigue, sleep disturbance, headache, irritable bowel syndrome and mood disorders. Different medical treatments are used to treat fibromyalgia and the recent guidelines suggest that the optimal treatment consists in a multidisciplinary approach with a combination of pharmacological and non-pharmacological treatment modalities. Among non-pharmacological treatment, nutrition is a promising tool for FM patients. The aim of this review is to update the present knowledge about fibromyalgia and nutrition by means of a systematic search performed on Medline from January 2000 to December 2014. Nutritional deficiencies have been described in FM patients and the benefits of specific diet and nutritional supplementation are shown. Obesity and overweight, often present in FM patients, are related to the severity of FM worsening the quality of life in terms of higher pain, fatigue, worsened sleep quality and higher incidence of mood disorders. Weight control is thus an effective tool to improve the symptoms. Moreover, it seems reasonable to eliminate some foods from the diet of FM patients, for example excitotoxins. Non-coeliac gluten sensitivity is increasingly recognised as a frequent condition with similar manifestations which overlap with those of FM. The elimination of gluten from the diet of FM patients is recently becoming a potential dietary intervention for clinical improvement. In summary, this review reveals the potential benefit of specific dietary interventions as non-pharmacological tools as part of a multidisciplinary treatment for FM patients.
The present paper aimed at reviewing literature data on the inflammatory hypothesis of mood spectrum, as well as the overlapping features with some chronic rheumatologic disorders, in particular fibromyalgia and chronic fatigue syndrome.
A literature search was carried out for English papers published in the years 2000-2014, while using the following words: mood spectrum, depression, bipolar disorders, fibromyalgia, chronic fatigue syndrome, neurotransmitters, inflammation, neuroinflammation, cytokines.
Overlapping features were highlighted between mood spectrum, fibromyalgia and chronic fatigue syndrome suggesting common underlying mechanisms at pathophysiological level involving both central nervous and the immune systems.
Taken together, the literature would suggest that the borders between different medical domains should be reconsidered in the light of common processes linking them.
Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Both mitochondrial dysfunction and inflammation have been implicated in the pathophysiology of FM. We have investigated the possible relationship between mitochondrial dysfunction, oxidative stress and inflammation in FM. We studied thirty women diagnosed with FM and twenty healthy women. Blood mononuclear cells (BMCs) from FM patients showed reduced level of CoQ10, mtDNA contents, and high level of mitochondrial ROS, serum TNF-alpha and transcript levels. A significant negative correlation between CoQ10 and TNF-alpha levels (r = -0.588; P<0.01), and a positive correlation between ROS and TNF-alpha levels (r = 0.791; P<0.001) were observed accompanied by a significant correlation of VAS with serum TNF-alpha and transcript levels (r = 0.4507; P<0.05 and r = 0.7089; P<0.001, respectively). TNF-alpha release was observed in an in vitro (BMCs) and in vivo (mice) CoQ10 deficiency model. Oral CoQ10 supplementation restored biochemical parameters and induced a significant improvement in clinical symptoms (P0.001). These results lead to the hypothesis that inflammation could be a mitochondrial dysfunction-dependent event implicated in the pathophysiology of FM in several patients indicating at mitochondria as a possible new therapeutic target.
Objectives:
To examine the effects of a challenge with monosodium glutamate (MSG) as compared to placebo on the symptoms of fibromyalgia (FM), in participants who initially experienced >30% remission of symptoms on an excitotoxin elimination diet.
Methods:
Fifty-seven FM patients who also had irritable bowel syndrome (IBS) were placed on a 4-week diet that excluded dietary additive excitotoxins including MSG and aspartame. Thirty-seven people completed the diet and 84% of those reported that >30% of their symptoms resolved, thus making them eligible to proceed to challenges. Subjects who improved on the diet were then randomised to a 2-week double-blind placebo-controlled crossover challenge with MSG or placebo for 3 consecutive days each week. The primary outcome measure was total symptom score. Secondary outcome measures included visual analogue pain scales (VAS for FM and IBS), an IBS Quality of Life Questionnaire (IBS QOL) and the Fibromyalgia Impact Questionnaire-Revised (FIQR). Repeated measures ANOVA was used to analyse crossover challenge results.
Results:
The MSG challenge, as compared to placebo, resulted in a significant return of symptoms (total symptom score, p<0.02); a worsening of fibromyalgia severity as determined by the FIQR (p<0.03); decreased quality of life in regards to IBS symptoms (IBS QOL, p<0.05); and a non-significant trend toward worsening FM pain based on visual analogue scale (VAS, p<0.07).
Conclusions:
These findings suggest that dietary glutamate may be contributing to FM symptoms in some patients. Future research on the role of dietary excitotoxins in FM is warranted.
We examined the association between serum trace elements and clinical findings such as number of sensitive tender points,
severity of fatigue and functional status in patients with fibromyalgia (FM). Thirty-two patients diagnosed as having FM according
to the ACR 1990 criteria and 32 normal healthy controls (NHC) were included in this study. The demographic data, disease duration,
number of tender points and accompanying symptoms (fatigue, sleep disorders, headache, paresthesia, irritable bowel syndrome,
sicca symptoms, Raynaud’s phenomena) of the patients were noted. Visual analog scale (10 cm) was implemented to estimate daily
severity of pain and fatigue. Fibromyalgia impact questionnaire was used for functional assessment. Serum selenium (μg/dL)
and serum zinc (μg/dL) levels were measured by atomic absorption spectrometer. Serum magnesium (mmol/L) level was measured
by the original kits of Abbott Aeroset auto-analyzer. The mean age of patients in FM group and NHC were calculated as 42.9
(SD = 7.7) years and 41.3 (SD = 9.7) years, respectively. Serum levels of zinc (P = 0.001) and magnesium (P = 0.002) were significantly decreased by FM groups, whereas there was no considerable difference with selenium levels of
both groups (P > 0.05). Association between serum zinc level and number of tender points (P = 0.008) and that between fatigue and magnesium level (P = 0.003) was found as meaningful. According to the results of this study, it was asserted that serum magnesium and zinc levels
may play an important role in the pathophysiology of FM.
We proposed to assess antioxidant status and nitric oxide in fibromyalgia (FM) patients in comparison to healthy controls.
Additionally, the association between the serum antioxidant levels and clinical findings in FM patients was also investigated.
Thirty-seven FM patients and 37 healthy controls were enrolled in this study. Severity of fatigue and pain were determined
by Visual Analogue Scale. Functional capacity in daily living activities was evaluated by fibromyalgia impact questionnaire.
Serum NO, catalase and glutathione were measured. Serum glutathione and catalase levels were significantly lower in FM patients
than controls. However, no significant difference was seen in serum NO levels between the two groups. A significant correlation
was evident between serum NO level and pain. Additionally, the correlation between glutathione level and morning stiffness
was found to be significant. These findings support other studies, we assume that these two antioxidants might have impact
on the pathogenesis of FM disease.
Lipid peroxidation often occurs in response to oxidative stress, and a great diversity of aldehydes are formed when lipid hydroperoxides break down in biological systems. Some of these aldehydes are highly reactive and may be considered as second toxic messengers which disseminate and augment initial free radical events. The aldehydes most intensively studied so far are 4-hydroxynonenal, 4-hydroxyhexenal, and malonaldehyde. The purpose of this review is to provide a comprehensive summary on the chemical properties of these aldehydes, the mechanisms of their formation and their occurrence in biological systems and methods for their determination. We will also review the reactions of 4-hydroxyalkenals and malonaldehyde with biomolecules (amino acids, proteins, nucleic acid bases), their metabolism in isolated cells and excretion in whole animals, as well as the many types of biological activities described so far, including cytotoxicity, genotoxicity, chemotactic, and effects on cell proliferation and gene expression. Structurally related compounds, such as acrolein, crotonaldehyde, and other 2-alkenals are also briefly discussed, since they have some properties in common with 4-hydroxyalkenals.
We proposed to assess serum antioxidant vitamins and magnesium (Mg) levels in patients with fibromyalgia (FM) in comparison to healthy controls. Additionally, the association between the serum antioxidant vitamins, magnesium levels, and clinical parameters in FM patients was also investigated. Forty female patients, aged between 30 and 50 years, were diagnosed with FM according to ACR-1990 criteria, and 40 healthy controls were included in the present study. Socio-demographic characteristics of participants, accompanying symptoms, and number of tender points (TP) of the patients were recorded. The intensity of pain was measured using the visual analogue scale (VAS). The functional status and depression levels were evaluated with Fibromyalgia Impact Questionnaire (FIQ) and Beck Depression Inventory (BDI), respectively. Serum vitamins A, C, and E and Mg levels were measured. There were no significant differences in the levels of vitamins A, C, and E and Mg between control subjects and patients with fibromyalgia (p > 0.05). In addition, no statistically significant correlations were found between mean levels of serum vitamins A, C, and E, and Mg and number of TP, scores of VAS, FIQ, and BDI in patients with FM (p > 0.05). According to the results of this study, it was asserted that other complex mechanism may play an important role in the pathophysiology of FM without plasma antioxidant vitamins and Mg levels.
Fibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress may have a role in the pathophysiology of fibromyalgia. However, it is still not clear whether oxidative stress is the cause or the effect of the abnormalities documented in fibromyalgia. Furthermore, the role of mitochondria in the redox imbalance reported in fibromyalgia also is controversial. We undertook this study to investigate the role of mitochondrial dysfunction, oxidative stress, and mitophagy in fibromyalgia.
We studied 20 patients (2 male, 18 female patients) from the database of the Sevillian Fibromyalgia Association and 10 healthy controls. We evaluated mitochondrial function in blood mononuclear cells from fibromyalgia patients measuring, coenzyme Q10 levels with high-performance liquid chromatography (HPLC), and mitochondrial membrane potential with flow cytometry. Oxidative stress was determined by measuring mitochondrial superoxide production with MitoSOX and lipid peroxidation in blood mononuclear cells and plasma from fibromyalgia patients. Autophagy activation was evaluated by quantifying the fluorescence intensity of LysoTracker Red staining of blood mononuclear cells. Mitophagy was confirmed by measuring citrate synthase activity and electron microscopy examination of blood mononuclear cells.
We found reduced levels of coenzyme Q10, decreased mitochondrial membrane potential, increased levels of mitochondrial superoxide in blood mononuclear cells, and increased levels of lipid peroxidation in both blood mononuclear cells and plasma from fibromyalgia patients. Mitochondrial dysfunction was also associated with increased expression of autophagic genes and the elimination of dysfunctional mitochondria with mitophagy.
These findings may support the role of oxidative stress and mitophagy in the pathophysiology of fibromyalgia.
Trigger points in painful muscle are a characteristic sign in patients with primary fibromyalgia. The MDO oxygen electrode was used to evaluate oxygenation in the subcutaneous tissue and in trigger points in the trapezius and brachioradial muscles. Ten patients and 8 normal controls were studied. The results in the patients were abnormal, with scattered or slalom-slope histograms, indicating low tissue oxygenation. The controls were normal, except in one case. The conclusion is that in patients with primary fibromyalgia, the muscle oxygenation is abnormal or low, at least in the trigger point area of the muscles.
To determine whether there is evidence of increased DNA fragmentation and ultrastructural changes in muscle tissue of patients with fibromyalgia (FM) compared with healthy controls.
Muscle tissues from 10 community residents with FM and 10 age and sex matched healthy controls were examined "blindly" for the presence of DNA fragmentation by two different methods: terminal deoxynucleotidyl transferase (TdT) staining (TUNEL) and the FragEL-Klenow DNA fragmentation detection kit. Ultrastructural analysis of tissue was performed by electron microscopy.
DNA fragmentation was detected by both methods in 55.4 (SEM 2.5)% of the nuclei in muscle tissue of patients with FM compared with 16.1 (4.1)% (p<0.001) of the nuclei in healthy controls. Contrary to expectation, no typical features of apoptosis could be detected by electron microscopy. The myofibres and actin filaments were disorganised and lipofuscin bodies were seen; glycogen and lipid accumulation were also found. The number of mitochondria was significantly lower in patients with FM than in controls and seemed to be morphologically altered.
The ultrastructural changes described suggest that patients with FM are characterised by abnormalities in muscle tissue that include increased DNA fragmentation and changes in the number and size of mitochondria. These cellular changes are not signs of apoptosis. Persistent focal contractions in muscle may contribute to ultrastructural tissue abnormalities as well as to the induction and/or chronicity of nociceptive transmission from muscle to the central nervous system.
The dominant research subject on schizophrenia, mood disorders, autism and other central nervous system diseases has been related to neurotransmitter system abnormalities. For example, the dopamine hypothesis states that schizophrenia is the result of dopaminergic hyperactivity. The therapeutic approach has also been directed towards finding agents which will modulate or regulate these neurotransmitter systems at any step. There is substantial and mounting evidence that subtle abnormalities of reactive oxygen species (ROS) and nitric oxide (NO) may underlie a wide range of neuropsychiatric disorders. NO has chemical properties that make it uniquely suitable as an intracellular and intercellular messenger. It is produced by the activity of nitric oxide synthases which are present in peripheral tissues and in neurons. On the other hand, NO is known to be an oxygen radical in the central and peripheral nervous systems. NO has been implicated in a number of physiological functions such as noradrenaline and dopamine releases, memory and learning and certain pathologies such as schizophrenia, bipolar disorder and major depression. Evidence has been considered here for the proposal that an abnormality of NO metabolism may be a contributory factor in some neuropsychiatric disorders. The direct evidence for NO abnormalities in schizophrenia and other psychiatric disorders remains relatively limited to date, although there are some clinical and experimental studies. The suggestion that NO and other ROS may play a role in some neuropsychiatric disorders clearly has important implications for new treatment possibilities. The primary objective of the present review was to summarize and critically evaluate the current knowledge regarding a potential contribution of NO to the neuropathophysiology of schizophrenia as well as other neuropsychiatric disorders.
We proposed to assess the oxidant/antioxidant status, lipid peroxidation and nitric oxide (NO) in untreated fibromyalgia (FM) patients and controls. The effect of amitriptyline (A, 20 mg daily) and sertraline (S, 100 mg daily) treatment on patients' superoxide dismutase (SOD), xanthine oxidase (XO), adenosine deaminase (ADA) enzyme activities, thiobarbituric acid reactive substances (TBARS) and NO levels was investigated. Thirty female patients with primary FM and age-matched 16 healthy female controls were included. Patients received an 8-week course of treatment with either A or S. FM patients had higher serum levels of TBARS (particularly malondialdehyde) and lower levels of nitrite compared to controls whereas enzyme activities were similar. A and S significantly improved Fibromyalgia Impact Questionnaire (FIQ) pain scores, Hamilton anxiety and depression rating scales. But neither A nor S had significant effects on measured oxidative stress parameters, except SOD activity that was significantly reduced after S treatment. Total myalgic scores negatively correlated with XO activity, and depression scales negatively correlated with levels of TBARS. Our results indicate that patients with FM are under oxidative stress. These findings represent a rationale for further research assessing the effect of free radical scavengers or antioxidant agents like vitamins and omega-3 fatty acids on peripheral and central mechanisms in FM.
Free radical damage is an important factor in many pathological and toxicological processes. Despite extensive research efforts in biomarkers in recent years, yielding promising results in experimental animals, there is still a great need for additional research on the applicability of, especially non-invasive, biomarkers of free radical damage in humans. This review gives an overview of the applications in experimental and human situations of four main groups of products resulting from free radical damage, these include: lipid peroxidation products, isoprostanes, DNA-hydroxylation products and protein hydroxylation products.
Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology. Recent studies have shown evidence demonstrating that oxidative stress may have a role in the pathophysiology of FM, however it is still not clear whether oxidative stress is the cause or the effect of the abnormalities documented in FM. Furthermore, it is also controversial the role of mitochondria in the pathophysiology of FM, however signs associated with mitochondrial dysfunction have been observed in FM. Mitochondria are also known to be strong producers of ROS, so have been related with the pathogenic mechanism of numerous diseases including FM. To this respect, it has been observed antioxidants therapies might be beneficial to improve the mitochondrial performance. Therefore, the dysfunction mitochondrial opens a great field of therapeutic research, for what it should start considering in the clinical medicine the boarding of the FM by means of therapy with antioxidant and drugs related to the mitochondrial biogenesis.
To develop criteria for the classification of fibromyalgia, we studied 558 consecutive patients: 293 patients with fibromyalgia and 265 control patients. Interviews and examinations were performed by trained, blinded assessors. Control patients for the group with primary fibromyalgia were matched for age and sex, and limited to patients with disorders that could be confused with primary fibromyalgia. Control patients for the group with secondary-concomitant fibromyalgia were matched for age, sex, and concomitant rheumatic disorders. Widespread pain (axial plus upper and lower segment plus left- and right-sided pain) was found in 97.6% of all patients with fibromyalgia and in 69.1% of all control patients. The combination of widespread pain and mild or greater tenderness in ⩾ 11 of 18 tender point sites yielded a sensitivity of 88.4% and a specificity of 81.1%. Primary fibromyalgia patients and secondary-concomitant fibromyalgia patients did not differ statistically in any major study variable, and the criteria performed equally well in patients with and those without concomitant rheumatic conditions. The newly proposed criteria for the classification of fibromyalgia are 1) widespread pain in combination with 2) tenderness at 11 or more of the 18 specific tender point sites. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities. At the diagnostic or classification level, the distinction between primary fibromyalgia and secondary-concomitant fibromyalgia (as defined in the text) is abandoned.
Chronic fatigue syndrome (CFS) is a poorly understood disease characterized by mental and physical fatigue, most often observed in young white females. Muscle pain at rest, exacerbated by exercise, is a common symptom. Although a specific defect in muscle metabolism has not been clearly defined, yet several studies report altered oxidative metabolism. In this study, we detected oxidative damage to DNA and lipids in muscle specimens of CFS patients as compared to age-matched controls, as well as increased activity of the antioxidant enzymes catalase, glutathione peroxidase, and transferase, and increases in total glutathione plasma levels. From these results we hypothesize that in CFS there is oxidative stress in muscle, which results in an increase in antioxidant defenses. Furthermore, in muscle membranes, fluidity and fatty acid composition are significantly different in specimens from CFS patients as compared to controls and to patients suffering from fibromyalgia. These data support an organic origin of CFS, in which muscle suffers oxidative damage.
Maintenance of health is dependent on numerous regulatory interactions between organ systems. This review discusses interorgan communication between the nervous, endocrine, and immune systems and environmental and genetic influences on this neuroendocrine immune circuitry. Stresses of multiple types, including psychological and exposure to chemicals and infectious agents, may combine to enhance neuroimmunotoxicology. Altered nervous system functions can alter immunity which could result in exacerbation of infections, cancers or other immune-associated problems. Inversely, abberant immune system activities could lead to pathologies associated with altered nervous activities, such as Alzheimer’s disease, chronic fatigue, or multiple sclerosis. The nervous, endocrine and immune circuitry is multi-directional, and a chemical, physical or emotional stress could upset the homeostasis.
Autoreactive T cells exist in healthy individuals and represent a potential reservoir of pathogenic effectors which, when stimulated by microbial adjuvants, could trigger an autoimmune disease. Experimental studies have indicated that xenobiotics, well defined from a chemical point of view, could promote the differentiation of autoreactive T cells towards a pathogenic pathway. It is therefore theoretically possible that compounds present in vaccines such as thiomersal or aluminium hydroxyde can trigger autoimmune reactions through bystander effects.Mercury and gold in rodents can induce immunological disorders with autoimmune reactions. In vitro, both activate signal transduction pathways that result in the expression of cytokines, particularly of IL-4 and IFNγ. In a suitable microenvironment heavy metals could therefore favour the activation of autoreactive T cells. In that respect, genetic background is of major importance. Genome-wide searches in the rat have shown that overlapping chromosomal regions control the immunological disorders induced by gold salt treatment, the development of experimental autoimmune encephalomyelitis and the CD45RChigh/CD45RClowCD4+T cells balance. The identification and functional characterization of genes controlling these phenotypes may shed light on key regulatory mechanisms of immune responses. This should help to improve efficacy and safety of vaccines.
To evaluate the intracellular levels of the high energy adenosine triphosphate nucleotide ATP and essential divalent cations, calcium and magnesium, in platelets of patients affected by primary fibromyalgia syndrome (FMs).
Platelet ATP and cation concentrations were measured in 25 patients affected by FMs and 25 healthy volunteers through a chemiluminescent and a fluorimetric assay, respectively.
Significant lower ATP levels were observed inside platelets of FM patients (fmol ATP/plt: 0.0169+/-0.0012 vs. healthy controls, fmol ATP/plt: 0.0306+/-0.0023, mean+/-SEM) (*** P<0.0001). A trend towards higher calcium concentrations (P=0.06) together with significant increased magnesium levels were also reported in platelets of patients by comparison with controls (P=0.02).
This preliminary study suggests that disturbances in the homeostasis of platelet ATP metabolism-signaling and calcium-magnesium flows might have a relevance in the pathogenesis of FMs.
To develop simple, practical criteria for clinical diagnosis of fibromyalgia that are suitable for use in primary and specialty care and that do not require a tender point examination, and to provide a severity scale for characteristic fibromyalgia symptoms.
We performed a multicenter study of 829 previously diagnosed fibromyalgia patients and controls using physician physical and interview examinations, including a widespread pain index (WPI), a measure of the number of painful body regions. Random forest and recursive partitioning analyses were used to guide the development of a case definition of fibromyalgia, to develop criteria, and to construct a symptom severity (SS) scale.
Approximately 25% of fibromyalgia patients did not satisfy the American College of Rheumatology (ACR) 1990 classification criteria at the time of the study. The most important diagnostic variables were WPI and categorical scales for cognitive symptoms, unrefreshed sleep, fatigue, and number of somatic symptoms. The categorical scales were summed to create an SS scale. We combined the SS scale and the WPI to recommend a new case definition of fibromyalgia: (WPI > or =7 AND SS > or =5) OR (WPI 3-6 AND SS > or =9).
This simple clinical case definition of fibromyalgia correctly classifies 88.1% of cases classified by the ACR classification criteria, and does not require a physical or tender point examination. The SS scale enables assessment of fibromyalgia symptom severity in persons with current or previous fibromyalgia, and in those to whom the criteria have not been applied. It will be especially useful in the longitudinal evaluation of patients with marked symptom variability.
The aim of this study was to investigate whether coenzyme Q10 (CoQ10) has an antifatigue effect in mice. ICR male mice were orally given CoQ10 in the form of Bio-Quinone (Pharma Nord, Vejle, Denmark) at doses of 0, 1.5, 15, or 45 mg/kg/day for 4 weeks. Mice were made to perform swimming exercise with loads attached to their tails, corresponding to approximately 5% of their body weights, and the total swimming time until exhaustion was measured. Furthermore, the post-exercise concentration of serum urea nitrogen (SUN), pre-/post-exercise and post-rest concentration of lactic acid (LA), and pre-exercise hepatic glycogen were determined. Mice treated with CoQ10 showed a significantly prolonged exhaustive swim time (15 mg/kg/day; P < .05), increased liver glycogen contents (15 and 45 mg/kg/day; P < .01 and P < .05, respectively), and decreased SUN levels (1.5, 15, and 45 mg/kg/day; P < .01) compared to control animals. The LA level was not significantly changed. These results suggest that CoQ10 improves swimming endurance and has an antifatigue effect.
Fibromyalgia (FMS) is a chronic widespread pain (CWP) and fatigue syndrome that affects three to six million adults in the United States. Core symptoms of FMS include pain, fatigue, and mood and sleep disturbances. To date, consensus has not been reached among researchers regarding the pathogenesis of FMS nor the specific role of cytokine activation on the neuroendocrine-immune response patterns in persons with FMS. The purpose of this article is to describe and synthesize the results of research studies focused on the relationship between cytokines and FMS and among cytokines and core symptoms of FMS. There is some support in the literature for relationships among FMS symptoms and cytokines; however, there are discrepant findings related to whether proinflammatory and anti-inflammatory cytokines are elevated or reduced in persons with FMS and whether their levels correlate with the core symptoms of this disorder. Although the use of cytokine biomarkers must be considered exploratory at this time due to the lack of consistent empirical findings, biobehavioral research focused on understanding the relationship of FMS with cytokines may lead to a better understanding of this complex syndrome. This knowledge may ultimately contribute to the development of interventions for symptom management that address not only the symptom manifestation but also a biological mediator of symptoms.
This work aimed to assess some pharmacological activities of coenzyme Q(10) (CoQ(10)) in animal experimental models.
The chick chorioallantoic membrane assay was used to evaluate anti-angiogenic activity of CoQ(10). Anti-inflammatory activity of CoQ(10) was confirmed using two animal models of inflammation. These were the vascular permeability and air pouch models, models of acute and sub-acute inflammation, respectively. Antinociceptive activity was assessed by the acetic acid-induced abdominal constriction response.
CoQ(10) dose-dependently displayed inhibition of chick chorioallantoic membrane angiogenesis. In the acetic acid-induced vascular permeability model in mice, CoQ(10) at 50, 100 and 200 mg/kg reduced vascular permeability from 0.74 +/- 0.01 (A(590)) to 0.67 +/- 0.01 (P < 0.01), 0.46 +/- 0.02 (P < 0.01) and 0.30 +/- 0.01 (P < 0.01), respectively. In the carrageenan-induced inflammation in the air pouch, CoQ(10) was able to diminish exudate volume, the number of polymorphonulcear leucocytes and nitrite content in the air pouches. CoQ(10) at 25, 50 and 100 mg/kg significantly reduced acetic acid-induced abdominal constriction in mice from 27.0 +/- 2.00 (number of abdominal constrictions) to 17.7 +/- 0.33 (P < 0.01), 9.3 +/- 0.67 (P < 0.01) and 1.3 +/- 0.33 (P < 0.01), respectively, suggesting a strong antinociceptive activity.
CoQ(10) possessed considerable anti-angiogenic, anti-inflammatory and antinociceptive activity, possibly via down-regulating the level of nitric oxide, which partly supported its use as a dietary supplement and in combination therapy.
A survey was performed in 5 European countries (France, Germany, Italy, Portugal, and Spain) to estimate the prevalence of fibromyalgia (FM) in the general population.
In each country, the London Fibromyalgia Epidemiological Study Screening Questionnaire (LFESSQ) was administered by telephone to a representative sample of the community over 15 years of age. A positive screen was defined as the following: (1) meeting the 4-pain criteria alone (LFESSQ-4), or (2) meeting both the 4-pain and the 2-fatigue criteria (LFESSQ-6). The questionnaire was also submitted to all outpatients referred to the 8 participating rheumatology clinics for 1 month. These patients were examined by a rheumatologist to confirm or exclude the FM diagnosis according to the 1990 American College of Rheumatology classification criteria. The prevalence of FM in the general population was estimated by applying the positive-predictive values to eligible community subjects (ie, positive screens).
Among rheumatology outpatients, 46% screened positive for chronic widespread pain (LFESSQ-4), 32% for pain and fatigue (LFESSQ-6), and 14% were confirmed FM cases. In the whole general population, 13 and 6.7% screened positive for LFESSQ-4 and LFESSQ-6, respectively. 3The estimated overall prevalence of FM was 4.7% (95% CI: 4.0 to 5.3) and 2.9% (95% CI: 2.4 to 3.4), respectively, in the general population. The prevalence of FM was age- and sex-related and varied among countries.
FM appears to be a common condition in these 5 European countries, even if data derived from the most specific criteria set (LFESSQ-6) are considered.
Clinical studies demonstrated the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapeutic in cardiovascular diseases, mitochondrial myopathies and neurodegenerative diseases. More recently, expression profiling revealed that Coenzyme Q10 (CoQ10) influences the expression of several hundred genes. To unravel the functional connections of these genes, we performed a text mining approach using the Genomatix BiblioSphere. We identified signalling pathways of G-protein coupled receptors, JAK/STAT, and Integrin which contain a number of CoQ10 sensitive genes. Further analysis suggested that IL5, thrombin, vitronectin, vitronectin receptor, and C-reactive protein are regulated by CoQ10 via the transcription factor NFkappaB1. To test this hypothesis, we studied the effect of CoQ10 on the NFkappaB1-dependent pro-inflammatory cytokine TNF-alpha. As a model, we utilized the murine macrophage cell lines RAW264.7 transfected with human apolipoprotein E3 (apoE3, control) or pro-inflammatory apoE4. In the presence of 2.5 microM or 75 microM CoQ10 the LPS-induced TNF-alpha response was significantly reduced to 73.3 +/- 2.8% and 74.7 +/- 8.9% in apoE3 or apoE4 cells, respectively. Therefore, the in silico analysis as well as the cell culture experiments suggested that CoQ10 exerts anti-inflammatory properties via NFkappaB1-dependent gene expression.
Primary fibromyalgia syndrome, also inappropriately called "fibrositis," is a clinically recognizable nonarticular rheumatic condition with diffuse and chronic musculoskeletal aching and stiffness, accompanied by exaggerated tenderness at characteristic sites on physical examination. Results of muscle biopsy from 12 well-defined cases of primary fibromyalgia syndrome without any history of trauma have been published recently. Light microscopic examination revealed no evidence of inflammation. Histochemical analysis demonstrated type II fiber atrophy in seven patients and the "moth-eaten" appearance of type I fibers in five patients. Electron microscopic findings were most impressive, and included myofibrillar lysis with deposition of glycogen and abnormal mitochondria, as well as subsarcolemmal accumulation of glycogen and mitochondria in all 12 patients and papillary projections of sarcolemmal membrane in 11 patients. Mechanisms of these significant muscle changes in primary fibromyalgia syndrome are uncertain but may include subclinical injury of muscle spasm.
The so called soft tissue rheumatism is located in skeletal musculature and collagen connective tissue. Its etiology and pathogenesis are not yet clear. The name 'fibrositis' suggests an inflammatory process. In a larger series of muscle biopsies from patients with 'muscular rheumatism' the authors could not demonstrate any inflammation with light optical methods. Electron microscopical examinations, however, furnished an impressive and clear pathology: the authors found step by step destruction of myofilaments in the I band region up to complete lysis of the contractile substance. They also found major changes in the endothelial cells of the muscle capillaries. The changes are probably due to a relative hypoxia of the muscle cells which results from the permanent hypertonus of isolated muscle parts. This isolated hypertonus corresponds to clinical 'muscular hardness' or 'myogeloses'. The cause is a neural irritation which can be started in different ways. In the collagen connective tissue of tendon sheath, tendons, bursa, and capsule the authors found in patients with 'soft tissue rheumatism' a peculiar mobilization and rejuvenescence of the local connective tissue cells up to mesenchymal transformation. They see the reason for this sporadical tumor like connective tissue cell proliferation in a local hypoxia of the bradytrophic, collagen tissue with few vessels. The cells adapt to an increased glycolysis. The increasing pyruvate is decomposed into acetyl coenzyme A. But as the mitochondria are destroyed by hypoxia, oxidation is no longer possible. The increased coenzyme A now causes an accelerated proliferation and ground substance formation of the connective tissue. The mesenchymal transformation is the morphological expression of this mechanism. The muscular as well as the collagen components of soft tissue rheumatism are based on local disturbances of oxygen supply, caused by caloric, mechanic or other influences. The contractile elements of the skeletal musculature are thus destroyed: the cells of the collagen connective tissue rheumatism is not a side phenomenon of other diseases, it is not based on an inflammatory disorder, but on local lack of oxygen.
Muscle pain has been associated with magnesium (Mg) and selenium (Se) deficiency: magnesium and selenium status were investigated in fibromyalgia (FM). Erythrocyte (E), leucocyte (L) and serum (S) magnesium, serum selenium and zinc, and vitamin B1, B2, A or E status were assessed in 22 patients with fibromyalgia and in 23 age-matched healthy controls. LMg is significantly increased (P < 0.05) and EMg slightly decreased in fibromyalgia. These magnesium abnormalities are associated with previously-reported impairment of thiamin metabolism. Antioxidant status (as well as plasma malondialdehyde) is unchanged in fibromyalgia and serum selenium levels, slightly but not significantly correlated with serum magnesium, is normal.
Free radicals are known to occur as natural by-products under physiological conditions and have been implicated in the neuronal loss observed in a variety of neuropathological conditions including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and ischemia. Oxyradical-induced cytotoxicity arises from both chronic and acute increases in reactive oxygen species which give rise to subsequent lipid peroxidation (LP). By reacting with polyunsaturated fatty acids in the the various cellular membranes, oxyradicals such as hydroxyl (OH.) and peroxynitrite (ONOO) give rise to a variety of lipid peroxidation products (LPP), including 4-hydroxynonenal (HNE) and malondialdehyde (MD). Once formed, these peroxidation metabolites have been demonstrated to have relatively long half-lives within cells (minutes to hours), allowing for multiple interactions with cellular components. Emerging data suggest that LP and LPP may underlie the neuronal alterations and neurotoxicity observed in numerous neurodegenerative conditions. Data supporting this involvement include the detection of LP and formation of LPP in a variety of neuropathological conditions including AD, ALS, PD, and ischemia. Secondly, direct application of LPP, either in vivo or in vitro, has been shown to be cytotoxic and mimic neuronal alterations observed in neuropathological conditions. Furthermore, prevention of LP and subsequent LPP formation have been demonstrated to be neuroprotective in a variety of neurodegenerative paradigms. Additionally, LP and LPP have been implicated in the modulation of a wide array of activities within the central nervous system including long term potentiation, neurite outgrowth, and proliferation. Understanding the mechanism(s) and involvement of LP in these processes will greatly enhance the understanding of oxyradical and ion homeostasis in neurophysiological and neuropathological conditions. The focus of this review is to describe the process by which lipid peroxidation occurs and establish a framework for its involvement in the central nervous system.
In a study on metabolism of aluminium in rats, two doses of aluminium, 100 mg/kg and 40 mg/kg, were administered through gastric tube in SD rats to observe its storage, distribution in various tissues and 48-hour excretion in urine and feces. Results showed that storage and distribution of aluminium in various tissues were different in two doses during different time periods. Apparent absorption rates of aluminum were 19.07-19.45 and 3.50-7.72 percent and apparent retention rates were 16.89-20.67 and 3.76-13.48 percent 24 and 48 hours after its intake, respectively, in high dose group, and those in low dose group were 29.40-36.58 and 3.76-13.48 percent and 29.27-36.43 and 3.69-13.35 percent, respectively. In high dose group, contents of aluminium in liver 0.5 hours, in kidney one hour, in brain 48 hours after intake were higher than those in other time periods. The highest content of aluminum was in the liver, and the next in the brain and kidney, in low aluminium group, and that in brain of the rats 24 and 48 hours after intake in the high dose group were significantly higher than those in the low dose group (P < 0.01). It suggests that different doses of aluminium had certain affinity to the brain of rats. Cumulative excretion of aluminium in urine and feces accounted for 1.08-1.22 and 0.11-0.31, and 97.01-99.13 and 86.55-96.07 percent of the total intake, respectively, in the high and low dose groups.
Various properties of skeletal muscle, including high metabolic activity and high levels of heme-containing proteins, render it particularly susceptible to free radical injury. Indeed, cellular injury from reactive oxygen species (ROS) has been implicated in many muscle disorders. Thus muscle cell survival is critically dependent on the ability of the cell to respond to periods of oxidative stress. To investigate this important homeostatic response, we studied the effect of oxidative challenges on the expression of genes encoding the antioxidant enzymes Cu,Zn-superoxide dismutase (CuZnSOD), Mn-superoxide dismutase (MnSOD), glutathione peroxidase (GPx), and catalase (CAT) in myotube cultures. Using Northern blot analysis, we found that treatment with the pro-oxidant paraquat resulted in time- and dose-dependent increases of transcript levels that were greatest for GPx and CAT (~4-5 fold). CuZnSOD and MnSOD transcripts were also increased, albeit more modestly (~2-3 fold). Transcript levels were also induced by treatment of the cells with two other pro-oxidants, menadione and H2O2, and correlated with the level of oxidative injury to the cells, measured as protein carbonyl group formation. Activities of all of the enzymes increased in response to the oxidative challenges, although the magnitudes of the increases were less robust than the increases of the respective transcript levels. In studying the effect of cellular differentiation on antioxidant gene expression and susceptibility to oxidative stress, we found that pro-oxidant treatment resulted in greater oxidative injury to differentiated myotubes than to undifferentiated myoblasts. Furthermore, the increased susceptibility of myotubes correlated with decreased antioxidant defenses-as muscle cells differentiated, both transcript and activity levels of antioxidant enzymes decreased. These data suggest that muscle cells regulate antioxidant defenses in response to oxidative stress and cellular differentiation.
The metallothioneins (MT) are small, cysteine-rich heavy metal-binding proteins which participate in an array of protective stress responses. Although a single essential function of MT has not been demonstrated, MT of higher eukaryotes evolved as a mechanism to regulate zinc levels and distribution within cells and organisms. These proteins can also protect against some toxic metals and oxidative stress-inducing agents. In mice, among the four known MT genes, the MT-I and -II genes are most widely expressed. Transcription of these genes is rapidly and dramatically up-regulated in response to zinc and cadmium, as well as in response to agents which cause oxidative stress and/or inflammation. The six zinc-finger metal-responsive transcription factor MTF-1 plays a central role in transcriptional activation of the MT-I gene in response to metals and oxidative stress. Mutation of the MTF-1 gene abolishes these responses, and MTF-1 is induced to bind to the metal response elements in proximal MT promoter in cells treated with zinc or during oxidative stress. The exact molecular mechanisms of action of MTF-1 are not fully understood. Our studies suggest that the DNA-binding activity of MTF-1 in vivo and in vitro is reversibly activated by zinc interactions with the zinc-finger domain. This reflects heterogeneity in the structure and function of the six zinc fingers. We hypothesize that MTF-1 functions as a sensor of free zinc pools in the cell. Changes in free zinc may occur in response to chemically diverse inducers. MTF-1 also exerts effects on MT-I gene transcription which are independent of a large increase in MTF-1 DNA-binding activity. For example, cadmium, which has little effect on the DNA-binding activity of MTF-1 in vivo or in vitro, is a more potent inducer of MT gene expression than is zinc. The basic helix-loop-helix-leucine zipper protein, USF (upstream stimulatory factor family), also plays a role in regulating transcription of the mouse MT-I gene in response to cadmium or H2O2. Expression of dominant negative USF-1 or deletion of its binding site from the proximal promoter attenuates induction of the mouse MT-I gene. USF apparently functions in this context by interacting with as yet unidentified proteins which bind to an antioxidant response element which overlaps the USF-binding site (USF/ARE). Interestingly, this composite element does not participate in the induction of MT-I gene transcription by zinc or redox-cycling quinones. Thus, regulation of the mouse MT-I gene by metals and oxidative stress involves multiple signaling pathways which depend on the species of metal ion and the nature of the oxidative stress.
Substance P (SP), a putative nociceptive transmitter, is increased in the CSF of patients with fibromyalgia syndrome (FMS). Because excitatory amino acids (EAAs) also appear to transmit pain, we hypothesized that CSF EAAs may be similarly involved in this syndrome. We found that the mean concentrations of most amino acids in the CSF did not differ amongst groups of subjects with primary FMS (PFMS), fibromyalgia associated with other conditions (SFMS), other painful conditions not exhibiting fibromyalgia (OTHER) or age-matched, healthy normal controls (HNC). However, in SFMS patients, individual measures of pain intensity, determined using an examination-based measure of pain intensity, the tender point index (TPI), covaried with their respective concentrations of glutamine and asparagine, metabolites of glutamate and aspartate, respectively. This suggests that re-uptake and biotransformation mask pain-related increases in EAAs. Individual concentrations of glycine and taurine also correlated with their respective TPI values in patients with PFMS. While taurine is affected by a variety of excitatory manipulations, glycine is an inhibitory transmitter as well as a positive modulator of the N-methyl-D-asparate (NMDA) receptor. In both PFMS and SFMS patients, TPI covaried with arginine, the precursor to nitric oxide (NO), whose concentrations, in turn, correlated with those of citrulline, a byproduct of NO synthesis. These events predict involvement of NO, a potent signaling molecule thought to be involved in pain processing. Together these metabolic changes that covary with the intensity of pain in patients with FMS may reflect increased EAA release and a positive modulation of NMDA receptors by glycine, perhaps resulting in enhanced synthesis of NO.
Accumulating data suggest that nitric oxide (NO) is important for both coronary and peripheral hemodynamic control and metabolic regulation during exercise. Although still controversial, NO of endothelial origin may potentiate exercise-induced hyperemia. Mechanisms of release include both acetylcholine derived from the neuromuscular junction and elevation in vascular shear stress. A splice variant of neuronal nitric oxide synthase (NOS), nNOSmu, is expressed in human skeletal muscle. In addition to being a potential modulator of blood flow, NO from skeletal muscle regulates muscle contraction and metabolism. In particular, recent human data indicate that NO plays a role in muscle glucose uptake during exercise independently of blood flow. Exercise training in healthy individuals elevates NO bioavailability through a variety of mechanisms including increased NOS enzyme expression and activity. Such adaptations likely contribute to increased exercise capacity and cardiovascular protection. Cardiovascular risk factors including hypercholesterolemia, hypertension, diabetes, and smoking as well as established disease are associated with impairment of the various NO systems. Given that NO is an important signaling mechanism during exercise, such impairment may contribute to limitations in exercise capacity through inadequate coronary or peripheral perfusion and via metabolic effects. Exercise training in individuals with elevated cardiovascular risk or established disease can increase NO bioavailability and may represent an important mechanism by which exercise training conveys benefit in the setting of secondary prevention.
Twelve female fibromyalgia syndrome (FMS) patients were given 500 mg per day of a blend containing 100 mg ascorbigen and 400 mg broccoli powder in a preliminary, one-month, open-label trial. This group of patients showed a mean 20.1 percent (p=0.044) decrease in their physical impairment score and a mean 17.8 percent (p=0.016) decrease in their total fibromyalgia impact scores as measured by the Fibromyalgia Impact Questionnaire. The mean physical impairment score two weeks post-treatment showed a significant return to near pre-treatment level (p=0.028). Analysis of ten of the patients' mean threshold pain levels at the 18 possible tender points obtained before and at the end of treatment showed a strong trend toward an increase in the mean threshold pain level (p=0.059). The reduced sensitivity to pain and improvement in quality of life measured in this study appear to be clinically relevant and a larger, double-blind study is warranted.
The aetiology and pathogenesis of the Chronic Fatigue Syndrome (CFS) are still largely unresolved. Accompanying metabolic disorders such as selective n-6 fatty acid depletion suggest that oxidative stress and more specifically lipid peroxidation might play a role in its pathogenesis. In order to investigate this hypothesis, oxidant-antioxidant status and its impact on lipoprotein peroxidation in vitro was examined in 61 patients with unexplained fatigue lasting more than 1 month. They were subdivided into 2 groups: group CFS+ (33 subjects) fulfilled the 1988 Center of Disease Control criteria for CFS and group CFS- did not but was similar as regards age, sex distribution and clinical characteristics. Antioxidant status was similar in the 2 groups except for lower serum transferrin in the CFS + (mean (95 % CI) 2.41 (2.28-2.54) versus 2.73 (2.54-2.92) g/L in the CFS-, p = 0.009) and higher lipoprotein peroxidation in vitro: 6630 (5949-7312) versus 5581 (4852-6310) nmol MDA/mg LDL and VLDL cholesterol x minutes, p = 0.035). CFS intensified the influence of LDL cholesterol (p = 0.012) and of transferrin (p = 0.045) on peroxidation in vitro, suggesting additional pro-oxidant effects. These results indicate that patients with CFS have increased susceptibility of LDL and VLDL to copper-induced peroxidation and that this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidising effects of CFS.
An open, uncontrolled study was undertaken to measure the subjective effects of coenzyme Q10 combined with a Ginkgo biloba extract in volunteer subjects with clinically diagnosed fibromyalgia syndrome. Anecdotal reports from patients with fibromyalgia syndrome have claimed benefits from the use of these supplements. The aim of this study was to determine if these reports could be substantiated in a pilot clinical trial. Patient questioning had determined that poor quality of life was a major factor in the condition and a quality-of-life questionnaire was used to measure potential benefit. Subjects were given oral doses of 200 mg coenzyme Q10 and 200 mg Ginkgo biloba extract daily for 84 days. Quality of life was measured, using the well-validated Dartmouth Primary Care Cooperative Information Project/World Organization of Family Doctors (COOP/WONCA) questionnaire that measures seven different subjective responses, at 0-, 4-, 8-, and 12-week intervals. The subjects were asked for an overall self-rating at the end of the study. A progressive improvement in the quality-of-life scores was observed over the study period and at the end, the scores showed a significant difference from those at the start. This was matched by an improvement in self-rating with 64% claiming to be better and only 9% claiming to feel worse. Adverse effects were minor. A controlled study is now planned.
The excessive generation of reactive oxygen metabolites (ROM) leads to an oxidative stress in the microvasculature of a variety of tissues and has been implicated as a causative event in a number of pathologies. There are numerous reviews on this topic that have been published recently. Herein, we will focus on a beneficial effect of ROM generation that leads to the development of an adaptive response that protects tissue from a subsequent oxidative stress (oxidant tolerance). We will focus on reductionist approaches (studies in isolated cells) used by our laboratory and those of others to define the mechanisms involved in this adaptational response and potential interactions between different cells within the tissue. As our prototype organ system, we target the heart, which has received the greatest amount of attention in this area. We will summarize evidence from isolated endothelial cells and cardiac myocytes that supports (i) the role of ROM in the development of oxidant tolerance, (ii) the possibility of an interaction between cardiac myocytes and endothelial cells in this phenomenon, and (iii) the potential interactions between ROMs and nitric oxide.
Building on the work of the late John Myers, MD, the author has used an intravenous vitamin-and-mineral formula for the treatment of a wide range of clinical conditions. The modified "Myers' cocktail," which consists of magnesium, calcium, B vitamins, and vitamin C, has been found to be effective against acute asthma attacks, migraines, fatigue (including chronic fatigue syndrome), fibromyalgia, acute muscle spasm, upper respiratory tract infections, chronic sinusitis, seasonal allergic rhinitis, cardiovascular disease, and other disorders. This paper presents a rationale for the therapeutic use of intravenous nutrients, reviews the relevant published clinical research, describes the author's clinical experiences, and discusses potential side effects and precautions.
In 21 patients with chronic fatigue syndrome (CFS) versus 20 normal subjects, we investigated the oxidant/antioxidant balance and its correlation with muscle symptoms. Patients versus controls showed significantly: lower Lag Phase and Vitamin E (Vit E) concentrations in plasma and low-density lipoproteins (LDL), higher LDL thiobarbituric acid reactive substances (TBARS), higher fatigue and lower muscle pain thresholds to electrical stimulation. A significant direct linear correlation was found between fatigue and TBARS, thresholds and Lag Phase, thresholds and Vit E in plasma and LDL. A significant inverse linear correlation was found between fatigue and Lag Phase, fatigue and Vit E, thresholds and TBARS. Increased oxidative stress and decreased antioxidant defenses are related to the extent of symptomatology in CFS, suggesting that antioxidant supplementation might relieve muscle symptoms in the syndrome.
Oxidative damage of biomolecules occurs as a result of potent free radical reactions. In this study, a novel, colorimetric and fully automated method for measuring total antioxidant response (TAR) against potent free radical reactions is described.
Potent free radical reactions were initiated with the production of hydroxyl radical (OH(*)) via Fenton reaction, and the rate of the reactions was monitored by following the absorbance of colored dianisidyl radicals. Ortho-dianisidine (10 mM) and ferrous ammonium sulfate (45 microM) were dissolved in KCl/HCl solution (75 mM, pH 1.8). This mixture was named as Reagent 1 and hydrogen peroxide solution (7.5 mM) as Reagent 2. The OH(*), produced by mixing of R1 and R2, oxidized o-dianisidine molecules into dianisidyl radicals, leading to a bright yellow-brown color development within seconds. Antioxidants, present in the sample, suppressed the color formation to a degree that is proportional to their concentrations. The method was applied to an automated analyzer and analytical performance characteristics of the assay were determined.
Vitamin C and Trolox, reduced glutathione, bilirubin, uric acid and (+/-)-catechin solutions suppressed the color formation depending on their concentrations. Serum TAR against potent free radical reactions was lower in patients with chronic renal failure (1.13 +/- 0.21 mmol Trolox equiv./l) and was higher in the individuals with neonatal icterus (2.82 +/- 1.18 mmol Trolox equiv./l) than in healthy subjects (1.54 +/- 0.15 mmol Trolox equiv./l).
The easy, inexpensive and fully automated method described can be used to measure TAR of samples against potent free radical reactions.
In the critical care setting, nurses frequently care for patients with acute and chronic diseases that affect multiple body systems. Many of these medical conditions have been associated with an imbalance between oxidizing chemicals called free radicals and antioxidants. Free radical damage is now assumed to be a contributing factor in all major diseases. In order to provide the most current and comprehensive care, critical care nurses need to be well informed about how free radicals cause damage and the antioxidant compounds that neutralize their destructive effects. This article provides an overview of oxygen free radicals and antioxidants and how they impact different clinical illnesses familiar to critical care nurses.
Fibromyalgia (FM) is a common chronic pain syndrome with an unknown etiology. Recent years added new information to our understanding of FM pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, hypothalamic-pituitary-adrenal axis hormones, oxidative stress, and mechanisms of pain modulation, central sensitization, and autonomic functions in FM revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of FM. Oxidative stress and nitric oxide may play an important role in FM pathophysiology, however it is still not clear whether oxidative stress abnormalities documented in FM are the cause or the effect. This should encourage further researches evaluating the potential role of oxidative stress and nitric oxide in the pathophysiology of FM and the efficacy of antioxidant treatments (omega-3 and -6 fatty acids, vitamins and others) in double blind and placebo controlled trials. These future researches will enhance our understanding of the complex pathophysiology of this disorder.
The purpose of the study was to determine the oxidative and antioxidative status of plasma in patients with fibromyalgia. Total antioxidant capacity (TAC) of plasma was significantly lower in patients with fibromyalgia (n = 20) than in healthy controls (n = 20) [1.5 (SD 0.3) and 1.9 (SD 0.3) mmol Trolox equiv./l, P = 0.001]. In contrast, the total peroxide level of plasma was significantly higher in patients than in healthy controls [37.4 (SD 6.7) and 33.0 (SD 2.7) micromol H2O2/l; P = 0.01]. The oxidative stress index (OSI) level was significantly higher in patients with fibromyalgia than in healthy controls [2.5 (SD 1.0) and 1.8 (SD 0.4); P = 0.007]. A significant negative correlation between visual analogue scale (VAS) and TAC level was determined (r = -0.79, P < 0.001). The present results indicate that patients with fibromyalgia are exposed to oxidative stress and this increased oxidative stress may play a role in the etiopathogenesis of the disease. Supplementation of antioxidant vitamins such as vitamins C and E to the therapy may be indicated.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
Novel classes of pain-relieving molecules are needed to fill the void between nonsteroidal anti-inflammatory agents and narcotics. Our studies have identified superoxide as a novel mediator of hyperalgesia (clinically defined as an augmented sensitivity to painful stimuli) and have exposed potential pathways through which this radical modulates the hyperalgesic response. The role of superoxide in pain was elucidated using a superoxide dismutase mimetic, M40403 [a manganese(II) complex with a bis(cyclo-hexylpyridine-substituted) macrocyclic ligand]. Intraplantar injection of carrageenan in rats led to time-dependent development of peripheral inflammation [measured parameters of inflammation included paw edema, cytokine release in the paw exudates, nitrotyrosine formation (a marker of peroxynitrite formation and oxidative stress), and poly-ADP-ribose-polymerase activation (the nuclear enzyme activated by superoxide/peroxynitrite)] and hyperalgesia. M40403 blocked all measured parameters of inflammation and hyperalgesia. Furthermore, when given therapeutically (2 h after the induction of hyperalgesia) either by intravenous or intrathecal administration, M40403 but not its inactive congener M40404 inhibited hyperalgesia with a rapid onset of action. Our results also show that, at the level of the spinal cord and time of peak hyperalgesia, endogenous manganese superoxide dismutase was nitrated and subsequently deactivated, losing its capacity to remove superoxide. The antihyperalgesic effects of M40403 were not reversed by naloxone excluding the potential involvement of an opiate pathway. Collectively, these studies have unraveled a critical role for superoxide in the nociceptive signaling cascade both peripherally and centrally. The discovery of this pathway opens a new therapeutic strategy for the development of novel nonnarcotic antihyperalgesic agents.