Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis.

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

Heat treatment in health and disease: How water-filtered infrared-A (wIRA) irradiation affects key cellular mechanisms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients compared to healthy donors.

Heat treatment or hyperthermia is a promising therapy for many diseases, especially cancer, and can be traced back thousands of years. Despite its long history, little is known about the cellular and molecular effects of heat on human cells. Therefore, we investigated the impact of water-filtered infrared-A (wIRA) irradiation (39 °C, 60 min) on key cellular mechanisms, namely autophagy, mitochondrial function and mRNA expression, in human fibroblasts and peripheral blood mononuclear cells (PBMCs) from healthy donors and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Our results show an induction of autophagy in healthy fibroblasts and PBMCs from healthy donors and ME/CFS patients. ME/CFS patients have higher mitochondrial function compared to healthy donors. The wIRA treatment leads to a slight reduction in mitochondrial function in PBMCs from ME/CFS patients, thereby approaching the level of mitochondrial function of healthy donors. Furthermore, an activation of the mRNA expression of the autophagy-related genes MAP1LC3B and SIRT1 as well as for HSPA1, which codes for a heat shock protein, can be observed. These results confirm an impact of heat treatment in human cells on key cellular mechanisms, namely autophagy and mitochondrial function, in health and disease, and provide hope for a potential treatment option for ME/CFS patients.

Does Coenzyme Q10 Plus Selenium Supplementation Ameliorate Clinical Outcomes by Modulating Oxidative Stress and Inflammation in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a neuroinflammatory, multifaceted chronic disorder of unknown cause. Accumulating data indicate a link between a redox imbalance, mitochondrial dysfunction, and inflammation status in ME/CFS. Coenzyme Q10 (CoQ10) and selenium as effective antioxidant and anti-inflammatory agents have shown potential clinical implications in chronic diseases; however, their therapeutic benefits in ME/CFS remain elusive. This open-label exploratory study aimed to evaluate the effectiveness of combined CoQ10 plus selenium supplementation on clinical features and circulating biomarkers in ME/CFS. Twenty-seven ME/CFS patients received an oral combination of 400 mg of CoQ10 and 200 µg of selenium daily for 8 weeks. The primary endpoint was patient-reported changes in outcome measures from baseline to 8 weeks' postintervention. Secondary endpoint included changes in circulating biomarkers from baseline to each participant. After an 8-week intervention, a significant improvement was found for overall fatigue severity (p = 0.021) and global quality of life (p = 0.002), while there was no significant effect on the sleep disturbances (p = 0.480) among participants. After 8 week's intervention, there was significantly increased total antioxidant capacity, and there were reduced lipoperoxide levels from the participants (p < 0.0001 for both). Circulating cytokine levels decreased significantly (p < 0.01 for all), but with no significant changes in the C-reactive protein, FGF21, and NT-proBNP biomarkers after supplementation. Based on these findings, we hypothesized that long-term supplementation of combined CoQ10 and selenium may indicate a potentially beneficial synergistic effect in ME/CFS. Antioxid. Redox Signal. 36, 729-739.

A proprietary herbal drug Young Yum Pill ameliorates chronic fatigue syndrome in mice.

BACKGROUND: Chronic fatigue syndrome (CFS) is a complex disease with few effective and safe therapies. Young Yum Pill (YYP), a proprietary herbal drug, has been used to relieve CFS-like symptoms. The pharmacological basis of this application of YYP is unknown. PURPOSE: This study aimed to investigate the pharmacological effects and mechanisms of action of YYP in a mouse model of CFS. STUDY DESIGN AND METHODS: A food restriction and exhaustive swimming-induced mouse CFS model was used to evaluate the effects of YYP. Lymphocyte proliferation was assessed by MTT assays. T-lymphocyte subsets were analyzed by flow cytometry. Serum biochemical parameters were determined using commercial kits. Protein levels were measured by immunoblotting. RESULTS: Intragastric administration of YYP (2.85, 5.70, 11.40 g/kg) daily for 21 consecutive days significantly prolonged swimming time and diminished body weight loss of CFS mice. Mechanistic investigations revealed that YYP increased thymus and spleen indices of CFS mice, enhanced proliferation of lipopolysaccharide- or concanavalin A-stimulated spleen lymphocytes, and increased CD3+CD4+ and CD3+CD8+ T-cells in the spleen. YYP increased glycogen content in gastrocnemius muscle and liver, and lowered levels of triglyceride, lactic acid and urea nitrogen in sera of CFS mice. YYP suppressed the elevation of serum level of malondialdehyde, the increase of activities of lactic dehydrogenase and creatine phosphokinase, and the decrease of activity of the serum antioxidant enzyme superoxide dismutase in CFS mice. Moreover, YYP upregulated protein level of activated AMPK in gastrocnemius muscle and liver of CFS mice. CONCLUSIONS: YYP ameliorates CFS by reversing metabolic changes, reducing oxidative damage, and improving some immune function parameters in mice. This study provides pharmacological justifications for the use of YYP in treating fatigue, including CFS.

Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome.

Post-viral fatigue syndrome (PVFS) is a widespread chronic neurological disease with no definite etiological factor(s), no actual diagnostic test, and no approved pharmacological treatment, therapy, or cure. Among other features, PVFS could be accompanied by various irregularities in creatine metabolism, perturbing either tissue levels of creatine in the brain, the rates of phosphocreatine resynthesis in the skeletal muscle, or the concentrations of the enzyme creatine kinase in the blood. Furthermore, supplemental creatine and related guanidino compounds appear to impact both patient- and clinician-reported outcomes in syndromes and maladies with chronic fatigue. This paper critically overviews the most common disturbances in creatine metabolism in various PVFS populations, summarizes human trials on dietary creatine and creatine analogs in the syndrome, and discusses new frontiers and open questions for using creatine in a post-COVID-19 world.

RADIATION DAMAGE OF THE NERVOUS SYSTEM AND ENDOCANABINOIDS. / RADIATsIINE URAZhENNIa NERVOVOÏ SYSTEMY I ENDOKANABINOÏDY.

The review analyzes the change of the existing paradigm of high radioresistance of the nervous system according tothe results of the study of neuropsychiatric disorders in in the aftermath of the Chornobyl accident in both earlyand remote post-accident period. The participation of the endocannabinoid system in ensuring homeostasis andpathology formation, potential possibilities of using cannabis drugs, agonists and antagonists of endocannabinoidreceptors for the treatment of early and long-term effects of radiation are considered.

Metabolic analysis of amino acids and vitamin B6 pathways in lymphoma survivors with cancer related chronic fatigue.

Chronic cancer-related fatigue (CF) is a common and distressing condition in a subset of cancer survivors and common also after successful treatment of malignant lymphoma. The etiology and pathogenesis of CF is unknown, and lack of biomarkers hampers development of diagnostic tests and successful therapy. Recent studies on the changes of amino acid levels and other metabolites in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have pointed to possible central defects in energy metabolism. Here we report a comprehensive analysis of serum concentrations of amino acids, including metabolites of tryptophan, the kynurenine pathway and vitamin B6 in a well characterized national Norwegian cohort of lymphoma survivors after high-dose therapy and autologous stem cell transplantation. Among the 20 standard amino acids in humans, only tryptophan levels were significantly lower in both males and females with CF compared to non-fatigued survivors, a strikingly different pattern than seen in CFS/ME. Markers of tryptophan degradation by the kynurenine pathway (kynurenine/tryptophan ratio) and activation of vitamin B6 catabolism (pyridoxic acid/(pyridoxal + pyridoxal 5'-phosphate), PAr index) differed in survivors with or without CF and correlated with known markers of immune activation and inflammation, such as neopterin, C-reactive protein and Interleukin-6. Among personal traits and clinical findings assessed simultaneously in participating survivors, higher neuroticism score, obesity and higher PAr index were significantly associated with increased risk of CF. Collectively, these data point to low grade immune activation and inflammation as a basis for CF in lymphoma survivors.

Qigong exercise for chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is often overlooked, has unclear etiology and no effective cure except some symptomatic treatments. Additionally, most people with CFS do not seek medical attention. Qigong exercise, an ancient Eastern body-mind-spirit practice, has been long practiced in Chinese communities and may powerfully trigger the self-healing process. Using full baseline data (n=1409), the average Hong Kong CFS respondent was found to be female, married, 42.5yo, highly educated and employed full-time, experiencing sleep disturbance (~95%), anxiety (>80%), and depressive symptoms (68%). Here, we summarized our previous studies to evaluate the potential of Qigong as a complementary and alternative therapy for CFS. Two randomized controlled trials were conducted (RCT1 n1=137, RCT2 n2=150). In both trials, extensive online questionnaires allowed individuals with CFS-like illness (i.e., symptoms match CFS, yet without clinical confirmation) to be identified. RCT1 included a 5-week intervention. The intervention in RCT2 was 8weeks. In RCT1 Qigong group had reduced fatigue (P<0.001) and depressive symptoms (P=0.002), and improved telomerase activity (P=0.029). An effective practice regimen was identified (≥3 days/week, at ≥30min/session). Methods were slightly adjusted for RCT2, which replicated RCT1 findings, and further documented improved subjective sleep quality (P=0.008) and adiponectin levels (P<0.05). A significant dose-response relationship was founded. Thus, Qigong exercise should be recognized as a possible standalone therapy and self-management skill in CFS. Strategies are needed to increase motivation for regular practice and to explore its possibility of self-management skill in brain health. Further clarity would come from studies comparing Qigong with other physical exercises.

Unraveling the Molecular Determinants of Manual Therapy: An Approach to Integrative Therapeutics for the Treatment of Fibromyalgia and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Application of protocols without parameter standardization and appropriate controls has led manual therapy (MT) and other physiotherapy-based approaches to controversial outcomes. Thus, there is an urgency to carefully define standard protocols that elevate physiotherapy treatments to rigorous scientific demands. One way in which this can be achieved is by studying gene expression and physiological changes that associate to particular, parameter-controlled, treatments in animal models, and translating this knowledge to properly designed, objective, quantitatively-monitored clinical trials (CTs). Here, we propose a molecular physiotherapy approach (MPTA) requiring multidisciplinary teams, to uncover the scientific reasons behind the numerous reports that historically attribute health benefits to MT-treatments. The review focuses on the identification of MT-induced physiological and molecular responses that could be used for the treatment of fibromyalgia (FM) and chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The systemic effects associated to mechanical-load responses are considered of particular relevance, as they suggest that defined, low-pain anatomic areas can be selected for MT treatment and yet yield overall benefits, an aspect that might result in it being essential to treat FM. Additionally, MT can provide muscle conditioning to sedentary patients without demanding strenuous physical effort, which is particularly detrimental for CFS/ME patients, placing MT as a real option for integrative medicine programs to improve FM and CFS/ME.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with associated malaise, headaches, sleep disturbance, and cognitive impairment, which severely impacts quality of life. A significant percentage of ME/CFS patients remain undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown, preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, which are apparently due to mitochondrial dysfunction in the absence of mitochondrial diseases, resulting in reduced oxidative metabolism. Such mitochondria may be further contributing to the ME/CFS symptomatology by extracellular secretion of mitochondrial DNA, which could act as an innate pathogen and create an autoinflammatory state in the hypothalamus. We propose that stimulation of hypothalamic mast cells by environmental, neuroimmune, pathogenic and stress triggers activates microglia, leading to focal inflammation in the brain and disturbed homeostasis. This process could be targeted for the development of novel effective treatments.

Antifatigue Potential Activity of Sarcodon imbricatus in Acute Excise-Treated and Chronic Fatigue Syndrome in Mice via Regulation of Nrf2-Mediated Oxidative Stress.

Sarcodon imbricatus (SI), a precious edible fungus, contains 35.22% of total sugar, 18.33% of total protein, 24 types of fatty acid, 16 types of amino acid, and 8 types of minerals. Encouragingly, it is rich in potential antioxidants such as total polyphenols (0.41%), total sterols (3.16%), and vitamins (0.44%). In the present study, the antifatigue properties of SI and its potential mechanisms of action were explored by the experiments on acute excise-treated mice and chronic fatigue syndrome (CFS) mice. SI (0.25, 0.5, and 1 g/kg) significantly enhanced exercise tolerance in the weight-loaded forced swimming test (FST) and rota-rod test (RRT) and reduced the immobility in the tail suspension test on CFS mice. SI markedly increased the levels of glycogen in the liver and adenosine triphosphate (ATP) in the liver and muscle and decreased the lactic acid (LD) and blood urea nitrogen (BUN) content in both acute swimming-treated mice and CFS mice. SI improved the endogenous cellular antioxidant enzyme contents in the two mouse models by improving the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels in serum, liver, and muscle, respectively. In CFS mice, the enhanced expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2), SOD1, SOD2, heme oxygenase-1 (HO-1), and catalase (CAT) in the liver were observed after a 32-day SI administration. Our data indicated that SI possessed antifatigue activity, which may be related to its ability to normalize energy metabolism and Nrf2-mediated oxidative stress. Consequently, SI can be expected to serve as a novel natural antifatigue supplement in health foods.

Vitamin and mineral status in chronic fatigue syndrome and fibromyalgia syndrome: A systematic review and meta-analysis.

BACKGROUND: Many chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) patients (35-68%) use nutritional supplements, while it is unclear whether deficiencies in vitamins and minerals contribute to symptoms in these patients. Objectives were (1) to determine vitamin and mineral status in CFS and FMS patients as compared to healthy controls; (2) to investigate the association between vitamin and mineral status and clinical parameters, including symptom severity and quality of life; and (3) to determine the effect of supplementation on clinical parameters. METHODS: The databases PubMed, EMBASE, Web of Knowledge, and PsycINFO were searched for eligible studies. Articles published from January 1st 1994 for CFS patients and 1990 for FMS patients till March 1st 2017 were included. Articles were included if the status of one or more vitamins or minerals were reported, or an intervention concerning vitamins or minerals was performed. Two reviewers independently extracted data and assessed the risk of bias. RESULTS: A total of 5 RCTs and 40 observational studies were included in the qualitative synthesis, of which 27 studies were included in the meta-analyses. Circulating concentrations of vitamin E were lower in patients compared to controls (pooled standardized mean difference (SMD): -1.57, 95%CI: -3.09, -0.05; p = .042). However, this difference was not present when restricting the analyses to the subgroup of studies with high quality scores. Poor study quality and a substantial heterogeneity in most studies was found. No vitamins or minerals have been repeatedly or consistently linked to clinical parameters. In addition, RCTs testing supplements containing these vitamins and/or minerals did not result in clinical improvements. DISCUSSION: Little evidence was found to support the hypothesis that vitamin and mineral deficiencies play a role in the pathophysiology of CFS and FMS, and that the use of supplements is effective in these patients. REGISTRATION: Study methods were documented in an international prospective register of systematic reviews (PROSPERO) protocol, registration number: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015032528.

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

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels. This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity. Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS. Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-α, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-ß, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms. HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.

Metabolic mechanism of a polysaccharide from Schisandra chinensis to relieve chronic fatigue syndrome.

Schisandra chinensis fruits are a famous traditional Chinese medicine to treat all kinds of fatigue. This study aimed to investigate the therapeutic effect and metabolic mechanism of a polysaccharide (SCP) from Schisandra chinensis fruits on chronic fatigue syndrome (CFS). SCP was isolated and the physicochemical properties were analyzed. A CFS model of rats was established and the urinary metabonomic studies were performed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) in combination with multivariate statistical analysis. The results showed that SCP is a protein-bound polysaccharide. The amino acid composition of SCP consisted of 12 amino acids. The growth and the behaviors of the rats in the CFS model group were worse than those in the control group and improved after SCP treatment. Analysis of the GC-TOF-MS revealed that twelve metabolites were significantly changed, and six metabolites were oppositely and significantly changed after the SCP treatment. The TCA cycle metabolic pathways and the alanine, aspartate and glutamate metabolism were identified as significant metabolic pathways involved with SCP. The therapeutic mechanism of SCP against CFS was partially due to the restoration of these disturbed pathways.

Improving the activity of Lycium barbarum polysaccharide on sub-health mice.

Sub-health has been described as a chronic condition of unexplained deteriorated physiological function, which falls between health and illness and includes fatigue as one of its principal manifestations. Mitochondrial dysfunctions have been discovered in fatigue-type sub-health such as impaired oxidative phosphorylation and mitochondrial damage. In the present study, we evaluated the effects of Lycium barbarum polysaccharide (LBP-4a), a polysaccharide fraction purified from Lycium barbarum, on anti-fatigue in sub-health mice, and the relevant mechanisms were studied. Forty mice were divided into control, model, LBP-4a(L) and LBP-4a(H) groups. Model mice were prepared through compound factors, including forced swim tests, sleep deprivation and wrapping restraint stress tests. After LBP-4a treatment for 4 weeks, the gastrocnemius muscles were obtained for morphological observation and the activities of SOD, GSH-Px and MDA content were detected. Furthermore, mitochondrial membrane potential and Ca(2+) content were measured in isolated skeletal muscle mitochondria. The results showed that LBP-4a could reduce skeletal muscle damage and MDA levels and enhance of SOD and GSH-Px activities compared with the model group. The levels of mitochondrial membrane potential and Ca(2+) were increased in LBP-4a-treated skeletal muscle mitochondria; moreover, the high-dosage group was better than that of the low dosage. In conclusion, LBP-4a exhibited anti-fatigue activity on sub-health mice, and the mechanism was closely correlated with a reduction in lipid peroxidation levels and an increase in antioxidant enzyme activities in skeletal muscle tissue, improving the intracellular calcium homeostasis imbalance and increasing mitochondrial membrane potential. These observations provided the background for the further development of LBP-4a as a type of anti-fatigue therapy used in sub-health treatment.

The effective mechanism of the polysaccharides from Panax ginseng on chronic fatigue syndrome.

Ginseng acidic polysaccharide WGPA isolated from the root of Panax ginseng C. A. Meyer was fractionated into WGPA-A and WGPA-N by anion-exchange chromatography. The antifatigue activity of ginseng acidic polysaccharide WGPA has been reported in our previous research. This present study was designed to identify its active component and elucidate the mechanism for preventing chronic fatigue syndrome (CFS). WGPA, WGPA-A and WGPA-N were orally administered to mice once daily for 15 days. The effects of these compounds on physiological biomarkers of oxidative stress and on the morphology of the mitochondria in striated skeletal muscle were assessed. The results of forced swimming test-induced indicated that WGPA and WGPA-A could lengthen the swimming time, while WGPA-N could not. In addition, malondialdehyde and lactate dehydrogenase levels in serum were enhanced; while those of superoxide dismutase and glutathione peroxidase were lowered. Interestingly, the structural degeneration of mitochondria were all ameliorated. These findings suggested that WGPA-A is the active component of WGPA, it might have potential therapeutic effects for CFS and the oxidative stress might be involved in the pathogenesis. Our results also provided essential data for a better understanding of the antifatigue effects of P. ginseng extracts.

Molecular mechanisms underpinning laser printer and photocopier induced symptoms, including chronic fatigue syndrome and respiratory tract hyperresponsiveness: pharmacological treatment with cinnamon and hydrogen.

Emissions of laser printers and photocopiers (LP&P) may be associated with health problems. The aim of this review is to describe the clinical picture that is triggered by exposure to LP&P and the molecular mechanisms underpinning the symptoms. Exposure to LP&P to vulnerable subjects may cause a symptom complex consisting of 1) irritation and hyperresponsiveness of the upper and lower respiratory tract; and 2) chronic fatigue (syndrome, CFS). Symptoms occur within hours after L&P exposure and may last for some days or become chronic with exacerbations following LP&P exposure. Substances that can be found in toners or are generated during the printing process are Silica nanoparticles, Titanium Dioxide nanoparticles, Carbon Black, metals, ozone, volatile organic compounds (VOC), etc. The latter may generate oxidative and nitrosative stress (O&NS), damage-associated molecular patterns molecules, pulmonary and systemic inflammation, and modulate Toll Like Receptor 4 (TRL4)­related mechanisms. It is concluded that LP&P emissions may cause activation of the TLR4 Radical Cycle and thus be associated with the onset of chronic inflammatory and O&NS illnesses, such as CFS, in some vulnerable individuals. Cinnamon, an antagonist of the TLR4 complex, and Hydrogen, a potent antiinflammatory and oxygen radical scavenger, may have efficacy treating LP&P-induced illness.

[Effect of acupuncture intervention on learning-memory ability and cerebral superoxide dismutase activity and malonaldehyde concentration in chronic fatigue syndrome rats].

OBJECTIVE: To observe the effect of acupuncture intervention on learning-memory ability and cerebral superoxide dismutase (SOD) activity and malonaldehyde (MDA) content in chronic fatigure syndrome (CFS) rats so as to reveal its mechanism underlying improvement of clinical CFS. METHODS: Thirty-six male SD rats were randomly divided into control group, model group and acupuncture group (n = 12 in each group). CFS model was established by double stress stimulation of suspending (1.0 - 2.5 h increasing gradually) and forced swimming [Morris water maze tasks, 7 min in (10 +/- 1) degrees C water], once daily for 12 days. Manual acupuncture stimulation was applied to "Baihui" (CV 20), bilateral "Zusanli" (ST 36) and "Sanyinjiao" (SP 6), once daily for 21 days (with 3 days' interval between every two weeks). Learning-memory ability was determined by Morris water maze tests, and SOD activity and MDA concentration in the brain tissues were detected by xanthine oxidase method and thiobarbiturif acid method, respectively. RESULTS: Compared with the control group, the escape latencies at time-points of day 1, 2, 3, 4 and 5 of Morris water maze tests were significantly longer, the target platform crossing times were markedly fewer and the target platform quadrant staying time obviously shorter, cerebral SOD activity was considerably decreased, and cerebral MDA content remarkably increased in the model group (P < 0.05, P < 0.01). Following acupuncture intervention, the escape latencies at time-points of day 1, 2, 3, 4 and 5 were significantly decreased, both target platform crossing times and staying time, and cerebral SOD activity were apparently increased, as well as cerebral MDA level was markedly lowered in comparison with the model group (P<0.05, P<0.01). CONCLUSION: Acupuncture intervention can improve the learning-memory ability in CFS rats, which may be related to its effect in regulating metabolism of free radicals in the brain tissues.

Shilajit attenuates behavioral symptoms of chronic fatigue syndrome by modulating the hypothalamic-pituitary-adrenal axis and mitochondrial bioenergetics in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Shilajit has been used as a rejuvenator for ages in Indian ancient traditional medicine and has been validated for a number of pharmacological activities. AIM OF THE STUDY: The effect of processed shilajit which was standardized to dibenzo-α-pyrones (DBPs;0.43% w/w), DBP-chromoproteins (DCPs; 20.45% w/w) and fulvic acids (56.75% w/w) was evaluated in a rat model of chronic fatigue syndrome (CFS). The mitochondrial bioenergetics and the activity of hypothalamus-pituitary-adrenal (HPA) axis were evaluated for the plausible mechanism of action of shilajit. MATERIALS AND METHODS: CFS was induced by forcing the rats to swim for 15mins for 21 consecutive days. The rats were treated with shilajit (25, 50 and 100mg/kg) for 21 days before exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility and the climbing period. The post-CFS anxiety level was assessed by elevated plus maze (EPM) test. Plasma corticosterone and adrenal gland weight were estimated as indices of HPA axis activity. Analysis of mitochondrial complex chain enzymes (Complex I, II, IV and V) and mitochondrial membrane potential (MMP) in prefrontal cortex (PFC) were performed to evaluate the mitochondrial bioenergetics and integrity respectively. RESULTS: Shilajit reversed the CFS-induced increase in immobility period and decrease in climbing behavior as well as attenuated anxiety in the EPM test. Shilajit reversed CFS-induced decrease in plasma corticosterone level and loss of adrenal gland weight indicating modulation of HPA axis. Shilajit prevented CFS-induced mitochondrial dysfunction by stabilizing the complex enzyme activities and the loss of MMP. Shilajit reversed CFS-induced mitochondrial oxidative stress in terms of NO concentration and, LPO, SOD and catalase activities. CONCLUSION: The results indicate that shilajit mitigates the effects of CFS in this model possibly through the modulation of HPA axis and preservation of mitochondrial function and integrity. The reversal of CFS-induced behavioral symptoms and mitochondrial bioenergetics by shilajit indicates mitochondria as a potential target for treatment of CFS.

Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells.

Neuroimaging evidence showed structural and/or functional abnormalities existing in the central nervous system, especially the hippocampus, in chronic fatigue syndrome (CFS) patients. However, its pathophysiologic mechanisms are unclear in part due to the lack of an applicable animal model. We established a chronic fatigue murine model by six repeated injections of Brucella abortus antigen to mice, which was manifested as reduced daily running activity and hippocampal atrophy. Thereafter, resveratrol, a polyphenolic activator of sirtuin 1, was used for treatment in this model. Daily running activity was increased by more than 20%, and the hippocampus was enlarged after 4-week resveratrol therapy. Furthermore, resveratrol inhibited neuronal apoptosis and expression of hippocampal acetylated p53 in the fatigue mice. Resveratrol also improved neurogenesis and expression of brain-derived neurotrophic factor mRNA in the hippocampus. We concluded that repeated injection of B. abortus antigen could induce hypoactivity and hippocampal atrophy in mice. Resveratrol may be effective for improving fatigue symptoms and enlarging the atrophic hippocampus by repressing apoptosis and promoting neurogenesis.