Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome

Abstract:

BACKGROUND: Patients diagnosed with chronic fatigue syndrome (CFS) or fibromyalgia experience chronic pain. Concomitantly, the rat model of CFS exhibits microglial activation in the lumbar spinal cord and pain behavior without peripheral tissue damage and/or inflammation. The present study addressed the mechanism underlying the association between pain and chronic stress using this rat model.

METHODS: Chronic or continuous stress-loading (CS) model rats, housed in a cage with a thin level of water (1.5 cm in depth), were used. The von Frey test and pressure pain test were employed to measure pain behavior. The neuronal and microglial activations were immunohistochemically demonstrated with antibodies against ATF3 and Iba1. Electromyography was used to evaluate muscle activity.

RESULTS: The expression of ATF3, a marker of neuronal hyperactivity or injury, was first observed in the lumbar dorsal root ganglion (DRG) neurons 2 days after CS initiation. More than 50% of ATF3-positive neurons simultaneously expressed the proprioceptor markers TrkC or VGluT1, whereas the co-expression rates for TrkA, TrkB, IB4, and CGRP were lower than 20%. Retrograde labeling using fluorogold showed that ATF3-positive proprioceptive DRG neurons mainly projected to the soleus. Substantial microglial accumulation was observed in the medial part of the dorsal horn on the fifth CS day. Microglial accumulation was observed around a subset of motor neurons in the dorsal part of the ventral horn on the sixth CS day. The motor neurons surrounded by microglia were ATF3-positive and mainly projected to the soleus. Electromyographic activity in the soleus was two to three times higher in the CS group than in the control group. These results suggest that chronic proprioceptor activation induces the sequential activation of neurons along the spinal reflex arc, and the neuronal activation further activates microglia along the arc. Proprioceptor suppression by ankle joint immobilization significantly suppressed the accumulation of microglia in the spinal cord, as well as the pain behavior.

CONCLUSION: Our results indicate that proprioceptor-induced microglial activation may be a key player in the initiation and maintenance of abnormal pain in patients with CFS.

Source: Yasui M, Menjyo Y, Tokizane K, Shiozawa A, Tsuda M, Inoue K, Kiyama H. Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome. J Neuroinflammation. 2019 Mar 30;16(1):67. doi: 10.1186/s12974-019-1456-x. https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1456-x (Full article)

Antioxidant and immunomodulatory properties of Spilanthes oleracea with potential effect in chronic fatigue syndrome infirmity

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) holds a mystery for researchers due to its multifactorial nature; hence, its diagnosis is still based on symptoms and aetiology remains obscured. Number of scientific evidences regarding the role of oxidative stress, immune dysfunction in CFS and alleviation of symptoms with the help of nutritional supplements guided us to study effect of ethanolic extract of Spilanthes oleracea (SPE) in CFS.

OBJECTIVES: Present study was designed to evaluate antioxidant, immunomodulatory properties of S. oleracea flower to ameliorate CFS infirmity in mice.

MATERIALS AND METHOD: In order to induce fatigue, experimental animals were stressed by chronic water – immersion stress model. Meanwhile, parameters like immobility period and tail withdrawal latency were assessed. On the 21st day, mice blood was collected and they were immediately sacrificed for biochemical estimations.

RESULTS: Biochemical analysis results revealed that CFS elevates lipid peroxidation, nitrite level and diminishes the endogenous antioxidant enzyme like catalase level in stressed animal’s brain homogenate. Stressful condition developed muscle fatigue leading in alteration of lactate dehydrogenase level (LDH), Blood urea nitrogen (BUN) and Triglycerides (TG) levels. Concurrent and chronic treatment of SPE for 21 days restored all these behavioural despairs and associated biochemical adaptation in mice in dose-dependent manner.

CONCLUSION: The outcome of this study indicates ability of SPE in amelioration of CFS by mitigating the oxidative stress and thus provide a powerful combat against CFS which may be due to its antioxidant and immunomodulatory properties.

Source: Nipate SS, Tiwari AH. Antioxidant and immunomodulatory properties of Spilanthes oleracea with potential effect in chronic fatigue syndrome infirmity. J Ayurveda Integr Med. 2018 Nov 16. pii: S0975-9476(17)30116-X. doi: 10.1016/j.jaim.2017.08.008. [Epub ahead of print] https://www.sciencedirect.com/science/article/pii/S097594761730116X?via%3Dihub (Full article)

The Human/Animal Interaction of Chronic Fatigue and Immune Dysfunction Syndrome: A Look At 127 Patients and Their 463 Animals

By R. Tom Glass, D.D.S., Ph.D. Professor Emeritus of Oral and Maxilofacial Pathology and Pathology University of Oklahoma, Health Sciences Center Tulsa, OK 74114

Throughout the recognized existence of Chronic Fatigue and Immune Dysfunction Syndrome, anecdotal reports have linked domestic animals with CFIDS, but no formal scientific studies were reported (1,2). Cats and dogs were implicated by their owners most frequently. The usual association with the presence of the animal in the household of a CFIDS patient, followed by the development of strange diseases or dysfunctions in the animal, many of which mimic CFIDS. The severity of the diseases often necessitated euthanasia. In a fewer number of cases, the onset of CFIDS in the patient was associated with an exposure to a domestic animal which was later found to show signs of CFIDS.

Observations from my animal biopsy service demonstrate two interesting findings in animals of CFIDS patients (unpublished findings). Gingival biopsies from cats demonstrated an unusual epithelial viral vesicle associated with an equally unusual submucosal inflammatory response. Several melanomas were found in dogs of CFIDS patients which had the unique feature of a striking progression of the tumor in the absence of an inflammatory response.

Both dogs and cats are known to be susceptible to a wide range of viruses. With the exception of rabies, no zoonotic (animal to human or human to animal) viral infection transmission has been demonstrated between typical domestic animals and humans (3).

These observations and recognitions prompted the following questions:

  1. Do CFIDS patients have domestic animals (pets)?
  2. What is the interaction between CFIDS patients and their pets?
  3. Do the domestic animals have any clinical signs of CFIDS?
  4. What type of signs or manifestations of CFIDS do animals of CFIDS patients demonstrate?
  5. What is the relationship between the interaction of CFIDS patients and their animals and the onset and course of CFIDS?

and resulted in a series of studies to answer the questions.

The first study was a retrospective study of Center for Disease Control and Prevention (CDC) criteria-met CFIDS patient: using a standardized questionnaire which included patient comments. The study subjects came from a university medical center and CFIDS support groups throughout the United States. Appropriate statistical tests, including mean, median, Z test, multivariant analysis, and Chi-square test, were used. This information was compared to national statistical Information on animal interaction compiled by the American Veterinary Medical Association.

One hundred twenty-seven (127) criteria-met CFIDS patients completed questionnaires on their animal Interactions- There were 114 females and 13 males in the study. All respondents were Caucasian with the exception of one Native American. The mean age of the CFIDS patients was 42.4 years with a median age of 43 years. 61.4% of the respondents were married; 311.6% were either single, divorced, or widowed.

The most striking result of this study was the association between CFIDS patients and animals (usually indoor pets) and the number of animals per CFIDS patient. 97% of the CFIDS patients had animal contact [expected normal contact: 57.9% (4)], with only 2 males and 2 females not reporting animal contact. Reported dog ownership per household for CFIDS males was 9.5 and for CFIDS females was 7.9 (expected national average: 1.52). Reported cat ownership per household for CFIDS males was 6.1 and for CFIDS females was 8.7 (expected national average: 1.95). 106 of the respondents (83.5%) reported that their animals (pets) had atypical diseases with signs and symptoms which mimicked CFIDS in humans. Of these 106 CFIDS patients 100 (94.3%) either were the primary caregiver for the sick animals or had intimate contact (sleeping with, being bitten or scratched by, or kissing the animal). The next most common animal contact was birds (parakeets and ducks were mentioned most often), followed by horses, cows, rabbits, goats, and guinea pigs. Two (2) CFIDS patients had contact with primates. The reported mean age of the dogs was 6 years (median = 6 years); of the cats was 6.2 years (median = 5 years); and of other types of animals was 3.2 years (median = 0.4 years).

All of these differences between expected and observed values were found to be statistically significant (p>001) including a statistically significant higher (.02<p£ 05) possession of cats by single, divorced, and widowed persons than married people. Statistical analysis (Chi-square) of the relationship between intimate contact by CFIDS patients and the presence of CFIDS like signs in their animals was highly significant (p£ 001). 67% of the respondents that had such contact stated that the animal showed CFIDS-like signs prior to the human and 33% of the respondents felt that the otherwise healthy animal contracted its CFIDS signs from the CFDS patient. The place where the pet was obtained was as follows: Friends (35%), Commercial (26%), Stray (21%), Pound (15%), Self-bred (3%), 41% of the CFIDS patients had animals that were still alive while 69% of the CFIDS patients had animals that had either died or were moribund at the time of the survey.

Finally, of equal importance were the CFIDS patient’s comments. These comments were often voluminous and detailed the interaction between the animals and the CFIDS patient. It is very clear that the CFIDS patients, in general, are “animal lovers” even though frquently the patient comments spoke of allergies to animals. Simliarly, the respondents gave excellent descriptions of their animal’s(s’) CFIDS-like signs from time of onset to ultimate temination.Respondents also noted that the animals were often the “living being” most consistently in close contact with the CFIDS patient.

The conclusion of this study was that CFIDS patients not only have pets, but that there is a significant animal interaction and that a large number of these animals have atypical or unusual diseases which at least mimic CFIDS.

In the second study, the CFIDS patients reported on a total of 463 animals: 115 healthy animals (which served as a control group for the study) and 348 animals which showed signs of either dysfunction or disease. The control group was comprised of 51 dogs (44%), 39 cats (34%), and 25 animals that were grouped together as “others”. The “others” group was predominantly large animals: horses, cows, goats, and pigs. All the control animals were still living and well at the time of the survey or had died of either traumatic or natural causes.

The group of animals which showed signs of either dysfunction or disease were made up of 189 dogs (54%), 144 cats (41%), and 15 animals that were grouped together as “others”. This “others” group was predominantly small domestic pets: birds, hamsters, and guinea pigs. The mean age of the dogs in this study was 6.5 years (median 6 years); of the cats was 6.2 years (median = 5 years); and of other types of animals was 3.2 years (median = 0.4 years).

The distribution of signs of the animals showing either dysfunction or disease are as follows: 137 animals (59 cats; 64 dogs; 14 others) were classified as having “General Signs.” 36 animals (15 cats; 14 dogs; 7 others) of the general signs category were classified as being “Sick NOS” because the animals were clearly Ill, but no diagnosis could be or had been rendered by a veterinarian. The “Sick NOS” animals were often described as having the same types of clinical signs as their owner. 26 animals (9 cats; 9 dogs; 7 others) in the general signs category died suddenly of unexplained causes. 26 animals (11 cats; 15 dogs) of the general signs category had a variety of altered immune conditions. including allergies, skin rashes, hair loss, systemic lupus erythematosus, and sneezing. 20 animals (3 cats; 17 dogs) developed Parvo or other viral Infections. 11 animals (9 cats; 2 dogs) transmitted their conditions to other animals either by birth or direct contact. 10 animals (9 cats; 1 dog) were listed as having eaten mice, rats, or other wild animals. 9 animals (3 cats; 6 dogs) had non-viral infections.

122 animals (41 cats; 81 dogs) had “Neurological” signs. 32 animals (17 cat.; 15 dogs) of the neurological category had lethargy, weakness, or sleep disorders. 30 animals (9 cats; 21 dogs) in the neurological category had seizures, tremors, or tail twitching. 19 animals (4 cat:; 15 dogs) demonstrated hind limb dragging, myalgia, arthralgia, or Bell’s palsy. 16 animals (6 cats; 10 dogs) were anxious, depressed, moody, or demonstrated inappropriate behavior, including urination and defecation outside their litterbox. 15 animals (4 cats; 11 dogs) had photophobia, ocular discharge, or blindness. 10 animals (1 cat; 9 dogs) had deafness, ear sensitivity, or loss of balance.

36 animals (21 cat.; 15 dogs) demonstrated “Gastrointestinal” signs. 13 animals (9 cats; 4 dogs) in the gastrointestinal category had inflamed gingiva, mouth odor, tooth loss, or drooling. 10 animal, (4 cats; 6 dogs) in the gastrointestinal category had diarrhea or abdominal distention. 9 animals (5 cat.; 4 dogs) demonstrated anorexia. 3 animals (2 cats; I dog) had increased appetite without weight gain. 1 cat had hard stools.

33 animals (18 cats; 14 dogs; 1 other) showed “Reticuloendothelial or Blood Disorders”. 12 animals (3 cats; 8 dogs; 1 other) of this category demonstrated bleeding or blood disorders. 10 animals (9 cats; I dog) in this category developed leukemia. While all of the leukemic cats were positive for feline leukemia virus [FLV], 5 of the cats had been vaccinated against FLV prior to the onset of their feline leukemia. 7 animals (5 cat.; 2 dogs) died of either feline AIDS or canine immune defidency (AIDS). 2 dogs showed massive and generalized lymphadenopathy. 1 cat and 1 dog died of lymphoma (lymphosarcoma).

Excluding leukemia and lymphoma, 15 animals (3 cats;12 dogs) developed tumors (“Neoplasia”). 8 animals (2 cats; 6 dogs) in this category had either fatal and/or multiple tumors which were not further classified, but which resulted in euthanasia of the animal. 4 dogs of this category died from malignant tumors of epithelial origin (3 squamous cell carcinomas and 1 transitional cell carcinoma), while 1 cat developed perianal adenomas, but was still living at the time of the survey. 1 dog died of a functional pituitary tumor and 1 dog died of melanoma.

Only 5 animals (2 cats; 3 dogs) were reported to have “Endocrine Disorders”. 2 cats and 2 dogs in this category had thyroid hyperplasia or thyroid nodules and 1 dog has pituitary hyperplasia.

Of equal importance, 113 of the 127 patients 89%) stated that their own CFIDS symptoms directly related their interaction with animals. Specifically, 79 of the respondents (71%) stated that they either had contact with multiple animals, were farmers, or were caretakers of multiple animals. 18 of these CFIDS patients (16%) note that the onset of their CFIDS symptoms were temporarily associated with the obtaining of a new pet, while 2 CFID patients (1%) noted that their CFIDS symptoms improved after the pet left or died. 9 respondents (8%) stated the other family members also contracted CFIDS in such manner as to implicate the pet as being possibly a common link in etiology. 3 CFIDS patients noted that the onset their CFIDS symptoms directly followed a flea bite episode and 2 CFDS patients reported that the prior owner of the home in which they contracted their CFIDS was inhabited by both CFIDS patients and sick animals.

As was noted in the first study, CFIDS patients care deeply for their animals. This observation can be understood by the detail and thoroughness with which the CFIDS patients filled out the information concerning the symptoms, laboratory results (such as blood count., blood chemistries, biopsy reports, etc.) and the courses of the animal’s(s’) condition. For the most part, it was the CF1DS patient who filled out the questionnaire. It must be remembered that these patients usually have severe fatigue and for them to have given such attention to detail was a major task.

Both studies also noted what an important role the pet plays in the CFIDS patient’s life. An analysis of the comments by the CFDS patients demonstrates unequivocally that the pet was often the CFIDS patient’s major contact with a living being. While it is imperative to consider the results of this study, it is equally imperative not to isolate CFIDS patients from their pets Rather, prevention of intimate contact, such as sharing food or kissing between the CFIDS patient and the pet, should be encouraged.

While the results of this study have certain subjective elements, such as reliance upon CFIDS patient and fault observations or the possibility of “symptom transference” (e.g., arthralgia in a pet is more likely to be noted by an arthralgic patient than a person free of joint pain), the recurrent finding of certain symptoms that may be common to both the CFIDS patient and the animal warrant attention It is important to consider the possibility that CFIDS may be transmitted from human to animal and/or from animal to human. If one considers the symptom of lethargy in the animals, the 32 CFIDS patients who observed this symptom all noted that the lack of energy was different than they had observed before in either the affected animal or in other animals in the same household who did not demonstrate the symptom. The seizure disorders and sudden unexplained deaths were more dramatic and objective signs of possible transmission of an agent that affects the nervous system. While seizure disorders and sudden unexplained deaths are not accepted features of CFIDS in humans, others have noted anecdotally a higher than usual number of seizure disorders and even sudden unexplained deaths in CFIDS patients.

While this study demonstrates the multiplicity of CFIDS-like signs in the animals, it is this same multi-organ involvement in the CFIDS patients that makes CFIDS so difficult to diagnose in humans. As with CFIDS in humans, the animals usually showed no laboratory evidence of a specific disease entity. There was, however, a predominance of neumlogic, neuromuscular, and rheumatologic symptoms in the animals just as there are in CFIDS patients. The result of these studies need to alert the veterinary profession of the need to inquire as to the health of the animal owner and their family. Conversations with a number of clinical veterinarians have pointed out that they are commonly confronted with conditions in domestic animals which do not fall into well established disease patterns. The most common of these deal with neurological and infectious diseases. These two areas were the most often reported as the pet signs found by CFIDS patients. Somewhat confounding was the low number of animals demonstrating endocrine disease. This under-reporting may be more of a lack of testing than a lack of disease as these tests are expensive and CFIDS patients are often financially unable to afford their own diagnostic tests., much less their animal’s(s’).

The results of these studies also need to alert the veterinaray profession that should there be a possibility of animal to human transmission of CFIDS, veterinarians might want to consider the wearing of protective clothing, gloves, eyewear, and masks when examining animals. We have received a number of reports from veterinarians around the country, especially from female veterinarians, that they have had to substantially limit their practices due to fatigue and other CFIDS-like symptoms. Similarly, precautions need to be taken to prevent CFIDS from being transmitted from one animal to another.

The conclusions of the second study were that animals of CFIDS patients demonstrated a wide range of disease and dysfunctional signs, similar to their CFIDS owners. The interactions between the animal and the CFIDS patients was often intimate. The study showed that the course of CFIDS in the animals varied widely, but after more thorough analyses of the data and of subsequent data, it appears that the animals have two distinct courses: 1. Their CFIDS signs produce progressive deterioration and the animal dies or 2. The animals appear to completely recover, usually after about five years.

In closing, both of the above studies had one common conclusion: animal interaction is a very important part of CFIDS patients’ lives’. I am often asked by CFIDS patients, knowing what I do about the CFIDS patient/animal interaction, if I would recommend that CFIDS patients have pets. While there is no way for me to survey animals, from my interaction with my own pet. and with the way CFIDS patients love their pets’ I would say that any pet would willingly run the risk of contracting CFIDS for the love, care and attention they will receive from CFIDS patients.

REFERENCES:

1. Ostrom, N. 50 Things You Should Know About the Chronic Fatigue Syndrome: New York: That New Magazine, 1992: pp 25, 26, 36, 37

2. Ostrom, N. What Really Killed Gilda Radner? New York: That New Magazine, Inc., 1991 pp. 159-164, 345-352

3. Cotran, RS., Kumar, V., Robbins, SL. Robbins Pathological Basis of Disease, 4th ed. Philadelphia: W. B. Saunders Co., 1989; pp. 309-310

4. Wise, JK. The Veterinary Sevice Market for Companion Animals. Schaumburg, IL; American Veterinary Association, 1992; pp. 5-65.

AUTHORS NOTE: This article is the first of three articles on my experiences with Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS; aka CFS). The first article deals with the interaction between CFIDS patients and their animals. The second article will deal with the actual autopsy findings of sick animals owned by CFIDS patients, the transmission of the CFIDS infectious agent to healthy animals, and the autopsy results of these animals. The third article will deal with the oral and head and neck manifestations of CFIDS, a lip biopsy of minor salivary glands for the confirmation of CFIDS, and some interesting therapy for the head and neck pain so often experienced by CFIDS patients [The second and third articles by Dr. Glass will he published in the next two consecutive issues of MPWC News – Ed. note.] In the early 1990’s, the following studies were conducted on CFIDS patients and their animals. The articles were sent to a number of both medical joumals and veterinary medical journals. The response from the editor of the medical journals was that while the articles were well-written, thorough and timely, they were better placed in veterinary medical journals. The veterinary medical joumal editors agreed with the medical journal editors in terms of the validity of the studies; however, they felt that if they published the articles, they might jeopardize the entire practice of veterinary medicine as small animals comprise the largest segments of such practices.

Source: This article appeared in the Spring 1998 Vol 3 Number 2 Edition of the Medical Professionals With CFIDS (MPWC) News

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.

Copyright © 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

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.

Copyright © 2017. Published by Elsevier Ltd.

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)

 

Characterization of a protein-bound polysaccharide from Herba Epimedii and its metabolic mechanism in chronic fatigue syndrome

Abstract:

OBJECTIVES: Herba Epimedii is one of the famous Traditional Chinese Medicines used to treat the chronic fatigue syndrome (CFS). The polysaccharides are the main active components in Herba Epimedii. The aim of this study is to discover the therapeutic effect and metabolic mechanism of Herba Epimedii polysaccharides against CFS.

METHODS: The polysaccharide conjugates named HEP2-a were isolated from the leaves of Herba Epimedii using a water extraction method, and the general physicochemical properties of HEP2-a were analysed. In addition, a CFS rat model was established, and then, urinary metabonomic studies were performed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) in combination with multivariate statistical analysis.

RESULTS: The physicochemical properties revealed that HEP2-a had an average molecular weight of 13.6×104 Da and consisted of mannose (4.41%), rhamnose (5.43%), glucose (31.26%), galactose (27.07%), arabinose (23.43%), and galacturonic acid (8.40%). The amino acids in HEP2-a include glutamate, cysteine, leucine, tyrosine, lysine, and histidine. Molecular morphology studies revealed many highly curled spherical particles with diameters of 5-10µm in solids and 100-200nm for particles in water. Five metabolites in the HEP2-a group were oppositely and significantly changed compared to the CFS model group.

CONCLUSION: Two metabolic pathways were identified as significant metabolic pathways involved with HEP2-a. The therapeutic effects of HEP2-a on CFS were partially due to the restoration of these disturbed pathways.

Copyright © 2017. Published by Elsevier B.V.

 

Source: Chi A, Shen Z, Zhu W, Sun Y, Kang Y, Guo F. Characterization of a protein-bound polysaccharide from Herba Epimedii and its metabolic mechanism in chronic fatigue syndrome. J Ethnopharmacol. 2017 Mar 27. pii: S0378-8741(16)31138-2. doi: 10.1016/j.jep.2017.03.041. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28359851

 

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

Abstract:

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.

Copyright © 2016 Elsevier B.V. All rights reserved.

 

Source: Chi A, Zhang Y, Kang Y, Shen Z. Metabolic mechanism of a polysaccharide from Schisandra chinensis to relieve chronic fatigue syndrome. Int J Biol Macromol. 2016 Dec;93(Pt A):322-332. doi: 10.1016/j.ijbiomac.2016.08.042. Epub 2016 Aug 18. https://www.ncbi.nlm.nih.gov/pubmed/27545408