Category: Animals

Electroacupuncture improves cognitive function by inhibiting NF-κB activity in rats with chronic fatigue syndrome

Abstract:

in English, Chinese

Objective: To observe the effect of electroacupuncture (EA) on the expression of NF-κB p65 in hippocampus and the morphology of hippocampus in rats with chronic fatigue syndrome (CFS), so as to explore its mechanism in improving cognitive dysfunction of CFS.

Methods: Forty-eight SD rats were randomly divided into control, model, EA and inhibitor groups (n=12 in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (50 Hz, 1 mA) at “Baihui” (GV20), Emotional Area I and bilateral Sensory Area for 30 min, once daily for 15 days. For rats in the inhibitor group, pyrrolidine dithiocarbamate (100 mg·kg-1·d-1) was injected intraperitoneally, once a day for 15 days. Learning and memory ability was evaluated by Morris water maze test. HE staining was used to observe the morphology of hippocampus. Western blot was used to determine the expression level of NF-κB p65 in hippocampus.

Results: After mode-ling, the general status score was increased （P<0.01）, the escape latency was prolonged(P<0.01), the times of crossing the platform was decreased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly increased (P<0.05) in the model group compared with the control group. Compared with the model group, the general status score was decreased （P<0.01）, the escape latency was shortened(P<0.01), the times of crossing the platform was increased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly decreased (P<0.05) in the EA and inhibitor groups. HE staining showed that in the model group, the hippocampal nerve cells were arranged disorderly, the structure was loose, and the number of apoptotic bodies and inflammatory cells was significantly increased. The degree of tissue damage of the EA and inhibitor groups was milder than that of the model group.

Conclusion: EA can improve the cognitive function in CFS rats, which may be associated with its effect in inhibiting the expression of NF-κB and reducing the inflammation response in hippocampus.

Source: Feng CW, Qu YY, Sun ZR, Wang YL, Zhang P, Wang QY, Lin WJ, Zhang L, Yang TS. [Electroacupuncture improves cognitive function by inhibiting NF-κB activity in rats with chronic fatigue syndrome]. Zhen Ci Yan Jiu. 2021 Sep 25;46(9):775-81. Chinese. doi: 10.13702/j.1000-0607.200827. PMID: 34558244. https://pubmed.ncbi.nlm.nih.gov/34558244/ [Article in Chinese]

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

Abstract:

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.

Source: Yin C, Fu X, Chou J, Li J, Chen Y, Bai J, Wu J, Wu Y, Wang X, Yu ZL. A proprietary herbal drug Young Yum Pill ameliorates chronic fatigue syndrome in mice. Phytomedicine. 2021 May 25;88:153602. doi: 10.1016/j.phymed.2021.153602. Epub ahead of print. PMID: 34102522. https://pubmed.ncbi.nlm.nih.gov/34102522/

Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME/CFS and its treatment. In addition, we discuss future perspectives of studies on ME/CFS.

Source: Yamano E, Watanabe Y, Kataoka Y. Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2021 Mar 26;22(7):3423. doi: 10.3390/ijms22073423. PMID: 33810365. https://pubmed.ncbi.nlm.nih.gov/33810365/

Exogenous Transforming Growth Factor-β in Brain-Induced Symptoms of Central Fatigue and Suppressed Dopamine Production in Mice

Abstract:

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is one of the most refractory diseases in humans and is characterized by severe central fatigue accompanied with various symptoms that affect daily life, such as impaired memory, depression, and somatic pain. However, the etiology and pathophysiological mechanisms of CFS remain unknown. To investigate the pathophysiological role of transforming growth factor (TGF)-β1, we injected a cytokine into the lateral ventricle of a C57BL/6 mouse. The intracranial injection of TGF-β1 increased the immobility duration in a forced swimming test (FST) and time spent at the closed arm in elevated plus maze (EPM) analysis.

The mice injected with TGF-β1 into their brain showed increased sensitivity to pain in a von Frey test, and had a decreased retention time on rotarod and latency time in a bright box in a passive avoidance test. In addition, the serum levels of muscle fatigue biomarkers, lactate dehydrogenase (LDH) and creatine kinase (CK), were significantly increased after administration of TGF-β1. Intracranial injection of TGF-β1 significantly reduced the production of tyrosine hydroxylase (TH) in the ventral tegmental area, accompanied by a decreased level of dopamine in the striatum. The suppression of TH expression by TGF-β1 was confirmed in the human neuroblastoma cell line, SH-SY5Y. These results, which show that TGF-β1 induced fatigue-like behaviors by suppressing dopamine production, suggest that TGF-β1 plays a critical role in the development of central fatigue and is, therefore, a potential therapeutic target of the disease.

Source: Lee WK, Kim Y, Jang H, Sim JH, Choi HJ, Shin Y, Choi JJ. Exogenous Transforming Growth Factor-β in Brain-Induced Symptoms of Central Fatigue and Suppressed Dopamine Production in Mice. Int J Mol Sci. 2021 Mar 4;22(5):2580. doi: 10.3390/ijms22052580. PMID: 33806649. https://pubmed.ncbi.nlm.nih.gov/33806649/

Acupuncture of the Beishu acupoint participates in regulatory effects of ginsenoside Rg1 on T cell subsets of rats with chronic fatigue syndrome

Abstract:

Background: There are close relationships between the spleen and limb muscles and thoughts. The study aims to test the effects of ginsenoside Rg1 in combination with acupuncture of the Beishu acupoint on T cell subsets of rats with chronic fatigue syndrome (CFS).

Methods: The model was set up by combining forced cold-water swimming with chronic restraint. The rats were randomly divided into blank control, model, ginsenoside, acupuncture, and ginsenoside plus acupuncture groups (n=10). For the acupuncture group, the Beishu acupoint was acupunctured on the 2nd day after modeling. For the ginsenoside group, the ginsenoside Rg1 solution was injected into the tail vein on the 2nd day after modeling. For the combination group, both processes were conducted. These groups were compared regarding exhausted swimming time, number of struggles, resting time, serum levels of IgA, IgG, IgM, IFN-α, IFN-β, and IFN-γ, lymphocyte transformation rate, T cell subsets, and skeletal muscle activities of malondialdehyde (MDA), total antioxidative capacity (T-AOC) and acetylcholinesterase (Ache).

Results: The exhausted swimming time, number of struggles, and resting time of combination group surpassed those in the ginsenoside and acupuncture groups significantly (P<0.05). The serum levels of IgA, IgG, IgM, IFN-β, IFN-γ, T-AOC, and Ache, together with CD3+ and CD8+ T cell percentages of combination groups, were significantly higher than those of ginsenoside and acupuncture groups. However, the IFN-α level, MDA activity, and CD4+ T cell percentage were significantly lower (P<0.05). Compared with the model group, the CD4+/CD8+ T cell ratios of acupuncture, ginsenoside, and combination groups decreased significantly (P<0.05). Compared with the combination group, the ratio of the ginsenoside group increased significantly (P<0.05).

Conclusions: Both acupuncture of the Beishu acupoint and intravenous injection of ginsenoside Rg1 have anti-fatigue effects, and their combination works synergistically. This study supplies an experimental basis for joint therapy using acupuncture and drugs to combat fatigue synergistically.

Source: He J, Yu Q, Wu C, Sun Z, Wu X, Liu R, Zhang H. Acupuncture of the Beishu acupoint participates in regulatory effects of ginsenoside Rg1 on T cell subsets of rats with chronic fatigue syndrome. Ann Palliat Med. 2020 Sep;9(5):3436-3446. doi: 10.21037/apm-20-1714. PMID: 33065794. http://apm.amegroups.com/article/view/52609/html (Full text)

Oxidative stress caused by a dysregulated Wnt/β-catenin signalling pathway is involved in abnormal placenta formation in pregnant mice with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is characterized by extreme fatigue and disabling symptoms. Women with CFS often have a high risk of gynaecological problems such as irregular menstruation, endometriosis and pelvic pain and sexual dysfunction. Our previous results have shown that, in pregnant mice, CFS significantly decreased the progestational hormone level in serum, as well as learning and memory, and the function of the hypothalamus-pituitary-gonadal axis. In addition, the F1 generation also suffered from congenital hypothyroidism. At present, there has been no report about placenta formation and embryonic development in pregnant mice with CFS. The aim of the present study was to investigate the influence of CFS on the morphology, oxidative stress and Wnt/β-catenin signalling pathway during placenta formation.

In this study, we found that CFS decreased the number of implantation sites for blastocysts, and increased the number of absorbed, stillborn and malformed fetuses. The morphology and structure of the placenta were abnormal in pregnant mice with CFS. Further study found that the oxidative stress in serum, uterus and placenta was increased in pregnant mice with CFS, while the levels of antioxidase were decreased. CFS also inhibited the Wnt/β-catenin signalling pathway in the placenta. These results suggested that inhibition of the Wnt/β-catenin signalling pathway and enhanced oxidative stress play an important role in abnormal placentation in pregnant mice with CFS.

Source: Zhao H, Zhang J, Qian N, Wu S, Wu Y, Yao G. Oxidative stress caused by a dysregulated Wnt/β-catenin signalling pathway is involved in abnormal placenta formation in pregnant mice with chronic fatigue syndrome. Zygote. 2020 Oct 15:1-8. doi: 10.1017/S096719942000057X. Epub ahead of print. PMID: 33054899. https://pubmed.ncbi.nlm.nih.gov/33054899/

Protective Effect of Hemin Against Experimental Chronic Fatigue Syndrome in Mice: Possible Role of Neurotransmitters

Abstract:

Chronic fatigue syndrome (CFS) is a disorder characterized by persistent and relapsing fatigue along with long-lasting and debilitating fatigue, myalgia, cognitive impairment, and many other common symptoms. The present study was conducted to explore the protective effect of hemin on CFS in experimental mice.

Male albino mice were subjected to stress-induced CFS in a forced swimming test apparatus for 21 days. After animals had been subjected to the forced swimming test, hemin (5 and 10 mg/kg; i.p.) and hemin (10 mg/kg) + tin(IV) protoporphyrin (SnPP), a hemeoxygenase-1 (HO-1) enzyme inhibitor, were administered daily for 21 days. Various behavioral tests (immobility period, locomotor activity, grip strength, and anxiety) and estimations of biochemical parameters (lipid peroxidation, nitrite, and GSH), mitochondrial complex dysfunctions (complexes I and II), and neurotransmitters (dopamine, serotonin, and norepinephrine and their metabolites) were subsequently assessed.

Animals exposed to 10 min of forced swimming session for 21 days showed a fatigue-like behavior (as increase in immobility period, decreased grip strength, and anxiety) and biochemical alteration observed by increased oxidative stress, mitochondrial dysfunction, and neurotransmitter level alteration. Treatment with hemin (5 and 10 mg/kg) for 21 days significantly improved the decreased immobility period, increased locomotor activity, and improved anxiety-like behavior, oxidative defense, mitochondrial complex dysfunction, and neurotransmitter level in the brain.

Further, these observations were reversed by SnPP, suggesting that the antifatigue effect of hemin is HO-1 dependent. The present study highlights the protective role of hemin against experimental CFS-induced behavioral, biochemical, and neurotransmitter alterations.

Source: Thakur V, Jamwal S, Kumar M, Rahi V, Kumar P. Protective Effect of Hemin Against Experimental Chronic Fatigue Syndrome in Mice: Possible Role of Neurotransmitters [published online ahead of print, 2020 Jun 6]. Neurotox Res. 2020;10.1007/s12640-020-00231-y. doi:10.1007/s12640-020-00231-y https://link.springer.com/article/10.1007%2Fs12640-020-00231-y

Homeostatic disturbance of thermoregulatory functions in rats with chronic fatigue

Abstract:

Chronic fatigue syndrome (CFS) is characterized by long-lasting fatigue, and a range of symptoms, and is involved in homeostasis disruption. CFS patients frequently complain of low grade fever or chill even under normal body temperature indicating that thermosensory or thermoregulatory functions might be disturbed in CFS. However, little is known about the detailed mechanisms. To elucidate whether and how thermoregulatory function was altered during the development of chronic fatigue, we investigated temporal changes in body temperature with advance of fatigue accumulation in a chronic fatigue rat model using a wireless transponder.

Our findings demonstrated that the body temperature was adaptively increased in response to fatigue loading in the early phase, but unable to retain in the late phase. The tail heat dissipation was often observed and the frequency of tail heat dissipation gradually increased initially, then decreased. In the late phase of fatigue loading, the body temperature for the tail heat dissipation phase decreased to a value lower than that for the non-dissipation phase. These results suggest that adaptive changes in thermoregulatory function occurred with fatigue progression, but this system might be disrupted by long-lasting fatigue, which may underlie the mechanism of fatigue chronification.

Copyright © 2020. Published by Elsevier B.V.

Source: Li D, Hu D, Shigeta M, Ochi Y, Watanabe Y, Li F, Cui Y. Homeostatic disturbance of thermoregulatory functions in rats with chronic fatigue. Neurosci Res. 2020 Apr 30. pii: S0168-0102(20)30157-7. doi: 10.1016/j.neures.2020.04.005. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32361157

 

An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome

Abstract:

Chronic fatigue syndrome (CFS) is one of the most intractable diseases and is characterized by severe central fatigue that impairs even daily activity. To date, the pathophysiological mechanisms are uncertain and no therapies exist. Therefore, a proper animal model reflecting the clinical features of CFS is urgently required.

We compared two CFS animal models most commonly used, by injection with lipopolysaccharide (LPS from Escherichia coli O111:B4) or polyinosinic: polycytidylic acid (poly I:C), along with bilateral adrenalectomy (ADX) as another possible model. Both LPS- and poly I:C-injected mice dominantly showed depressive behaviors, while ADX led to fatigue-like performances with high pain sensitivity.

In brain tissues, LPS injection notably activated microglia and the 5-hydroxytryptamine (HT)1A receptor in the prefrontal cortex and hippocampus. Poly I:C-injection also remarkably activated the 5-HT transporter and 5-HT1A receptor with a reduction in serotonin levels in the brain. ADX particularly activated astrocytes and transforming growth factor beta (TGF-β) 1 in all brain regions.

Our results revealed that LPS and poly I:C animal models approximate depressive disorder more closely than CFS. We suggest that ADX is a possible method for establishing a mouse model of CFS reflecting clinical features, especially in neuroendocrine system.

Source: Lee JS, Jeon YJ, Park SY, Son CG. An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome. Biomolecules. 2020 Jan 1;10(1). pii: E71. doi: 10.3390/biom10010071. https://www.mdpi.com/2218-273X/10/1/71 (Full article)

Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine

Abstract:

The diagnosis of chronic fatigue syndrome (CFS) is mainly symptom-based, and the etiology is still unclear. Here, we evaluated the pathological changes in the brain of a mouse model of CFS and studied the effects of Kampo medicine.

A mouse model of CFS was established through six repeated injections of Brucella abortus (BA) every two weeks for a period of 12 weeks. Neuroinflammation was measured by estimating interleukin (IL)-1β, IL-6, and interferon-gamma (IFN-γ), and oxidative stress by nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) 6 weeks after the last injection. Hippocampal neurogenesis was evaluated through Ki-67, doublecortin (DCX), and 5-bromodeoxyuridine (BrdU) assays. The effects of Kampo medicines (Hochuekkito (TJ-41) and Hachimijiogan (TJ-7)) on neuroinflammation during CFS were studied.

The wheel-running activity of mice was decreased by about 50% compared to baseline at 6 weeks after the last BA injection. The levels of IL-1β, IL-6, 3-NT, and 4-HNE were increased in both the cortex and the hippocampus of CFS mice at 6 weeks after the last BA injection. Hippocampal neurogenesis was unchanged in CFS mice. Treatment with TJ-41 and TJ-7 reduced the expressions of IL-1β, IL-6, and IFN-γ in the hippocampus but not in the cortex.

The results of the present study indicate that neuroinflammation and oxidative stress play important roles in the pathogenesis of CFS. The data further suggest that treatment with TJ-41 and TJ-7 could help reduce the inflammation associated with CFS in the hippocampus, but failed to improve the symptoms in CFS mice.

Source: He Q, Sawada M, Yamasaki N, Akazawa S, Furuta H, Uenishi H, Meng X, Nakahashi T, Ishigaki Y, Moriya J. Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine. Biol Pharm Bull. 2020;43(1):110-115. doi: 10.1248/bpb.b19-00616. https://www.jstage.jst.go.jp/article/bpb/43/1/43_b19-00616/_article (Full article)