experimental fatigue – American ME and CFS Society

Effect of Swarna Jibanti (Coelogyne cristata Lindley) in alleviation of chronic fatigue syndrome in aged Wistar rats

Abstract:

BACKGROUND: Swarna Jibanti scientifically known as Coelogyne cristata Lindley (Orchidaceae), an orchid mentioned in Ayurvedic medicine is used to promote healthy life span.

OBJECTIVE: The present work was planned to study the efficacy of hydro-alcoholic extract of pseudobulbs of C.cristata (CCE) to assess its role on chronic fatigue syndrome (CFS) induced behavioural and biochemical changes in aged Wistar rats compared to Panax ginseng (PG), a prototype anti-stress agent.

MATERIALS AND METHODS: CFS was induced by forced swimming for consecutive 21 days for fixed duration (15 min sessions). The criteria of CFS due to fatigue were counted using locomotor activity, depression and anxiety through automated photactometer, immobility time and plus maze activity respectively. Acute toxicity study of CCE (upto 2 g/kg, Limit test) was also performed. For CFS, animals were divided into five groups, naive control, control, CCE treated (25 mg/kg b.w., 250 mg/kg b.w.) and standard PG treated (100 mg/kg b.w.) groups. All drugs were given orally for consecutive 21 days along with CFS. After assessing behavioural parameters, all animals were sacrificed at day 21 and in vivo antioxidant potential of CCE was determined by lipid peroxides, nitrite, catalase (CAT) and superoxide dismutase (SOD) in brain tissue.

RESULTS: CCE was found to be non-toxic. CCE treated aged rats significantly improved (p < 0.001) the spontaneous locomotor movement with respect to control rats, while, decreased the mobility period or depression score. In CFS, CCE also enhanced the time spent (p < 0.001) in open arms while reducing the time spent in closed arm as compared to CFS control, indicating lowering anxiety score. Moreover, marked diminution in lipid peroxidation, nitrite and SOD level was exhibited after CCE treatment and significantly enhanced catalase level significantly (p < 0.01) with respect to CFS control. PG also showed similar actions.

CONCLUSION: The results confirmed the potential therapeutic actions of CCE against experimentally induced CFS in aged rats that might be due to its CNS mediatory antioxidant properties.

Source: Mitra A, Sur TK, Upadhyay S, Bhattacharyya D, Hazra J. Effect of Swarna Jibanti (Coelogyne cristata Lindley) in alleviation of chronic fatigue syndrome in aged Wistar rats. J Ayurveda Integr Med. 2017 Nov 1. pii: S0975-9476(17)30217-6. doi: 10.1016/j.jaim.2017.06.011. [Epub ahead of print] http://www.sciencedirect.com/science/article/pii/S0975947617302176 (Full article)

Effect of Acupuncture on the Expression of Transcription Factor T-bet/GATA-3 in Plasma of Rats with Chronic Fatigue Syndrome

Abstract:

OBJECTIVE: To observe the effect of acupuncture on the expression of T-box expressed in T cell (T-bet)/GATA binding factor-3 (GATA-3) in plasma of rats with chronic fatigue syndrome (CFS) and explore the mechanism of acupuncture treatment for CFS.

METHODS: Forty-eight healthy male SD rats were randomly divided into blank control group, CFS model group, acupuncture group, and ginsenoside group (12 rats in each group). CFS rat model was established by combining restriction and cold water swimming. Acupuncture was applied to “Baihui”(GV 20), “Guanyuan” (CV 4) and “Zusanli” (ST 36, bilate-ral) acupoints, once a day for two weeks. The ginsenoside group was gavage administrated with ginsenoside, once a day for two weeks. After 14 days, behavioural changes were observed, and the expression levels of T-bet/GATA-3 genes in plasma were detected by RT-PCR.

RESULTS: Compared with the blank control group, the time for immobility of forced suspensory test was signi-ficantly longer (P<0.05) and the time for exhaustive swimming was significantly shortened (P<0.05) in the CFS model group. Compared with the model group, the two indexes above-mentioned were reversed (P<0.05) both in the acupuncture group and the ginsenoside group, and the effects in the acupuncture group were more significant than those in the ginsenoside group (P<0.05). Compared with the blank control group, the expression level of T-cell transcription factor T-bet gene in plasma was higher in the CFS model group (P<0.05), companied with lower GATA-3 gene expression (P<0.05). The ratio of T-bet/GATA-3 was higher in the model group than in the blank control group(P<0.05). Compared with the CFS model group, all the indexes above-mentioned were reversed (P<0.05) in the two treatment groups. Acupuncture group showed a better effect on reducing T-bet gene expression than the ginsenoside group (P<0.05).

CONCLUSIONS: Acupuncture can decrease the expression level of T-bet gene while increase the expression of GATA-3 gene, which may be associated with its role in treating CFS.

Source: Wang XY, Liu CZ, Lei B. Effect of Acupuncture on the Expression of Transcription Factor T-bet/GATA-3 in Plasma of Rats with Chronic Fatigue Syndrome. Zhen Ci Yan Jiu. 2017 Jun 25;42(3):246-8. [Article in Chinese] https://www.ncbi.nlm.nih.gov/pubmed/29071982

NLRP3 inflammasome activation mediates fatigue-like behaviours in mice via neuroinflammation

Abstract:

Numerous experimental and clinical studies have suggested that the interaction between the immune system and the brain plays an important role in the pathophysiology of chronic fatigue syndrome (CFS). The NLRP3 inflammasome is an important part of the innate immune system. This complex regulates proinflammatory cytokine interleukin-1β (IL-1β) maturation, which triggers different kinds of immune-inflammatory reactions.

We employed repeated forced swims to establish a model of CFS in mice. NLRP3 knockout (KO) mice were also used to explore NLRP3 inflammasome activation in the mechanisms of CFS, using the same treatment. After completing repeated swim tests, the mice displayed fatigue-like behaviours, including locomotor activity and reduced fall-off time on the rota-rod test, which was accompanied by significantly higher mature IL-1β level in the prefrontal cortex (PFC) and malondialdehyde (MDA) level in serum. We also found increased NLRP3 protein expression, NLRP3 inflammasome formation and increased mature IL-1β production in the PFC, relative to untreated mice. The NLRP3 KO mice displayed significantly moderated fatigue behaviours along with decreased PFC and serum IL-1β levels under the same treatment.

These findings demonstrated the involvement of NLRP3 inflammasome activation in the mechanism of swimming-induced fatigue. Future therapies targeting the NLRP3/IL-1β pathway may have significant potential for fatigue prevention and treatment.

Source: Zhang Z, Ma X, Xia Z, Chen J, Liu Y, Chen Y, Zhu J, Li J, Yu H, Zong Y, Lu G. NLRP3 inflammasome activation mediates fatigue-like behaviours in mice via neuroinflammation. Neuroscience. 2017 Jul 3. pii: S0306-4522(17)30453-0. doi: 10.1016/j.neuroscience.2017.06.048. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28684277

The variation of the 5-hydroxytryptamine system between chronic unpredictable mild stress rats and chronic fatigue syndrome rats induced by forced treadmill running

Abstract:

The aim of this study was to observe the variation in the 5-hydroxytryptamine (5-HT) system between a chronic unpredictable mild stress (CUMS) model and a chronic fatigue syndrome (CFS) model. The total distance, the crossing pieces, and rearing times in the open-field test of the CUMS group and the CFS group were all less than those of the control group to different degrees.

The concentrations of tryptophan, 5-HT, and 5-HIAA of the CUMS group were obviously lower than those of the control group. In the CFS model, the concentrations of tryptophan, 5-HT, and 5-HIAA were obviously higher than those of the control group. The expressions of tryptophan hydroxylase-2 (TPH-2) and 5-HT1A receptor in protein level and mRNA level were also different among the three groups. The expressions of TPH-2 and 5-HT1A were higher in the CFS group than in the CUMS group. The expressions of TPH-2 and 5-HT1A receptor were lower in the CUMS group than in the control group. We can find that in different situations of mood disorders, the variation of 5-HT system may also be opposite.

Source: Cao Y, Li Q. The variation of the 5-hydroxytryptamine system between chronic unpredictable mild stress rats and chronic fatigue syndrome rats induced by forced treadmill running. Neuroreport. 2017 May 12. doi: 10.1097/WNR.0000000000000797. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28505018

Detection of Urine Metabolites in a Rat Model of Chronic Fatigue Syndrome before and after Exercise

Abstract:

Purpose. The aim of the present study was to elucidate the metabolic mechanisms associated with chronic fatigue syndrome (CFS) via an analysis of urine metabolites prior to and following exercise in a rat model.

Methods. A rat model of CFS was established using restraint-stress, forced exercise, and crowded and noisy environments over a period of 4 weeks. Behavioral experiments were conducted in order to evaluate the model. Urine metabolites were analyzed via gas chromatography-mass spectrometry (GC-MS) in combination with multivariate statistical analysis before and after exercise.

Results. A total of 20 metabolites were detected in CFS rats before and after exercise. Three metabolic pathways (TCA cycle; alanine, aspartate, and glutamate metabolism; steroid hormone biosynthesis) were significantly impacted before and after exercise, while sphingolipid metabolism alone exhibited significant alterations after exercise only.

Conclusion. In addition to metabolic disturbances involving some energy substances, alterations in steroid hormone biosynthesis and sphingolipid metabolism were detected in CFS rats. Sphingosine and 21-hydroxypregnenolone may be key biomarkers of CFS, potentially offering evidence in support of immune dysfunction and hypothalamic-pituitary-adrenal (HPA) axis hypoactivity in patients with CFS.

Source: Shao C, Ren Y, Wang Z, Kang C, Jiang H, Chi A. Detection of Urine Metabolites in a Rat Model of Chronic Fatigue Syndrome before and after Exercise. Biomed Res Int. 2017;2017:8182020. doi: 10.1155/2017/8182020. Epub 2017 Mar 22. https://www.hindawi.com/journals/bmri/2017/8182020/ (Full article)

Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome

Abstract:

BACKGROUND: The NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3) is an intracellular protein complex that plays an important role in innate immune sensing. Its activation leads to the maturation of caspase-1 and regulates the cleavage of interleukin (IL)-1β and IL-18. Various studies have shown that activation of the immune system plays a pivotal role in the development of fatigue. However, the mechanisms underlying the association between immune activation and fatigue remained elusive, and few reports have described the involvement of NLRP3 inflammasome activation in fatigue.

METHODS: We established a mouse fatigue model with lipopolysaccharide (LPS, 3 mg/kg) challenge combined with swim stress. Both behavioural and biochemical parameters were measured to illustrate the characteristics of this model. We also assessed NLRP3 inflammasome activation in the mouse diencephalon, which is the brain region that has been suggested to be responsible for fatigue sensation. To further identify the role of NLRP3 inflammasome activation in the pathogenesis of chronic fatigue syndrome (CFS), NLRP3 KO mice were also subjected to LPS treatment and swim stress, and the same parameters were evaluated.

RESULTS: Mice challenged with LPS and subjected to the swim stress test showed decreased locomotor activity, decreased fall-off time in a rota-rod test and increased serum levels of IL-1β and IL-6 compared with untreated mice. Serum levels of lactic acid and malondialdehyde (MDA) were not significantly altered in the treated mice. We demonstrated increased NLRP3 expression, IL-1β production and caspase-1 activation in the diencephalons of the treated mice. In NLRP3 KO mice, we found remarkably increased locomotor activity with longer fall-off times and decreased serum IL-1β levels compared with those of wild-type (WT) mice after LPS challenge and the swim stress test. IL-1β levels in the diencephalon were also significantly decreased in the NLRP3 KO mice. By contrast, IL-6 levels were not significantly altered.

CONCLUSIONS: These findings suggest that LPS-induced fatigue is an IL-1β-dependent process and that the NLRP3/caspase-1 pathway is involved in the mechanisms of LPS-induced fatigue behaviours. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment.

Source: Zhang ZT, Du XM, Ma XJ, Zong Y, Chen JK, Yu CL, Liu YG, Chen YC, Zhao LJ, Lu GC. Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome. J Neuroinflammation. 2016 Apr 5;13(1):71. doi: 10.1186/s12974-016-0539-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822300/ (Full article)

Evaluation of the effect of ethanolic extract of fruit pulp of Cassia fistula Linn. on forced swimming induced chronic fatigue syndrome in mice

Abstract:

The fruit of Cassia fistula Linn. is a legume, has antioxidant and lots of other medicinal properties. As oxidants are involved in the pathogenesis of chronic fatigue syndrome, the present study was done to evaluate the effect of ethanolic extract of fruit pulp of C. fistula Linn. (EECF) on forced swimming induced chronic fatigue syndrome (CFS).

Albino mice of 25-40 grams were grouped into five groups (n=5). Group A served as naive control and group B served as stress control. Group C received EECF 200 mg/kg and group D received EECF 400 mg/kg respectively. Group E received imipramine 20 mg/kg (standard). All animals were treated with their respective agent orally daily for 7 days. Except for group A, animals in other groups were subjected to force swimming 6 min daily for 7 days to induce a state of chronic fatigue. Duration of immobility was assessed on day 1(st), 3(rd), 5(th) and 7(th). Anxiety level (by elevated plus maze and mirrored chamber) and loco-motor activity (by open field test) were assessed 24 h after last force swimming followed by biochemical estimations of oxidative biomarkers in brain homogenate at the end of study.

Treatment with EECF resulted in significant reduction in the duration of immobility, reduced anxiety and increased loco-motor activity. Malondialdehyde level was also reduced and catalase level was increased in the extract treated group and standard group compared to stress control group. The study indicates that EECF has protective effect against experimentally induced CFS.

Source: Sarma P, Borah M, Das S. Evaluation of the effect of ethanolic extract of fruit pulp of Cassia fistula Linn. on forced swimming induced chronic fatigue syndrome in mice. Res Pharm Sci. 2015 May-Jun;10(3):206-13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621627/ (Full article)

Induction Murine Models of Chronic Fatigue Syndrome by Brucella abortus Antigen Injections: Is Anemia Induced or Not?

Abstract:

To investigate whether Brucella abortus (BA) antigen injections lead to anemia, and to establish an appropriate Chronic Fatigue Syndrome (CFS) animal model by BA injections, 6 repeated injections of BA antigen were fulfilled every 2 weeks. At a high dose of 1∗10(10) particles/mouse, anemia was induced within 2 weeks and then recovered a lot at the end of the research, while at a moderate dose of 1∗10(8) (3 injections) shifting to 1∗10(9)/mouse (3 injections) anemia was absent. In both groups running wheel activity remained very low even 6 weeks after the last injection.

Source: Moriya J, He Q, Uenishi H, Akazawa S, Yamakawa J, Kobayashi J, Ishigaki Y. Induction Murine Models of Chronic Fatigue Syndrome by Brucella abortus Antigen Injections: Is Anemia Induced or Not? Biomed Res Int. 2015;2015:191489. doi: 10.1155/2015/191489. Epub 2015 Jun 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480237/ (Full article)

Isoflavones inhibit poly(I:C)-induced serum, brain, and skin inflammatory mediators – relevance to chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a neuroimmunoendocrine disease affecting about 1% of the US population, mostly women. It is characterized by debilitating fatigue for six or more months in the absence of cancer or other systemic diseases. Many CFS patients also have fibromyalgia and skin hypersensitivity that worsen with stress. Corticotropin-releasing hormone (CRH) and neurotensin (NT), secreted under stress, activate mast cells (MC) necessary for allergic reactions to release inflammatory mediators that could contribute to CFS symptoms.

OBJECTIVE: To investigate the effect of isoflavones on the action of polyinosinic:polycytidylic acid (poly(I:C)), with or without swim stress, on mouse locomotor activity and inflammatory mediator expression, as well as on human MC activation.

METHODS: Female C57BL/6 mice were randomly divided into four groups: (a) control/no-swim, (b) control/swim, (c) polyinosinic:polycytidylic acid (poly(I:C))/no swim, and (d) polyinosinic:polycytidylic acid (poly(I:C))/swim. Mice were provided with chow low or high in isoflavones for 2 weeks prior to ip injection with 20 mg/kg poly(I:C) followed or not by swim stress for 15 minutes. Locomotor activity was monitored overnight and animals were sacrificed the following day. Brain and skin gene expression, as well as serum levels, of inflammatory mediators were measured. Data were analyzed using the non-parametric Mann-Whitney U-test.

RESULTS: Poly(I:C)-treated mice had decreased locomotor activity over 24 hours, and increased serum levels of TNF-α, IL-6, KC (IL-8/CXCL8 murine homolog), CCL2,3,4,5, CXCL10, as well as brain and skin gene expression of TNF, IL-6, KC (Cxcl1, IL8 murine homolog), CCL2, CCL4, CCL5 and CXCL10. Histidine decarboxylase (HDC) and NT expression were also increased, but only in the skin, over the same period. High isoflavone diet reversed these effects.

CONCLUSION: Poly(I:C) treatment decreased mouse locomotor activity and increased serum levels and brain and skin gene expression of inflammatory mediators. These effects were inhibited by isoflavones that may prove useful in CFS.

Source: Vasiadi M, Newman J, Theoharides TC. Isoflavones inhibit poly(I:C)-induced serum, brain, and skin inflammatory mediators – relevance to chronic fatigue syndrome. J Neuroinflammation. 2014 Oct 31;11:168. doi: 10.1186/s12974-014-0168-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236420/ (Full article)

A Study of the Protective Effect of Triticum aestivum L. in an Experimental Animal Model of Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Oxidative stress plays a major role in the pathogenesis of chronic fatigue syndrome (CFS). Keeping in view the proven antioxidant activity of Triticum aestivum L., this study has been undertaken to explore the potential therapeutic benefit of this plant in the treatment of CFS.

OBJECTIVE: To study the protective effect of the ethanolic extract of the leaves of Triticum aestivum (EETA) in an experimental mice model of CFS.

MATERIALS AND METHODS: Five groups of albino mice (20-25 g) were selected for the study, with five animals in each group. Group A served as the naïve control and Group B served as the stressed control. Groups C and D received EETA (100 mg/kg and 200 mg/kg b.w.). Group E received imipramine (20 mg/kg b.w.). Except for Group A, mice in each group were forced to swim 6 min each for 7 days to induce a state of chronic fatigue. Duration of immobility was measured on every alternate day. After 7 days, various behavioral tests (mirror chamber and elevated plus maize test for anxiety, open field test for locomotor activity) and biochemical estimations (malondialdehyde [MDA] and catalase activity) in mice brain were performed.

RESULTS: Forced swimming in the stressed group resulted in a significant increase in immobility period, decrease in locomotor activity and elevated anxiety level. The brain homogenate showed significantly increased MDA and decreased catalase levels. The extract-treated groups showed significantly (P < 0.05) improved locomotor activity, decreased anxiety level, elevated catalase levels and reduction of MDA.

CONCLUSION: The study confirms the protective effects of EETA in CFS.

Source: Borah M, Sarma P, Das S. A Study of the Protective Effect of Triticum aestivum L. in an Experimental Animal Model of Chronic Fatigue Syndrome. Pharmacognosy Res. 2014 Oct;6(4):285-91. Doi: 10.4103/0974-8490.138251. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166815/ (Full article)