Category: Animals

Olmesartan alleviates symptoms of chronic fatigue syndrome in mice

Abstract:

Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is a lifestyle-related ailment that affects physical and mental abilities.

The etiology is largely unidentified but there are certain multifactorial mechanisms responsible such as mitochondrial aerobic pathways aberrations, hypothalamic-pituitary-adrenal (HPA) axis deregulation, immune hyperactivation, free radicals, pathogen infections, and central neurohumoral alterations.

Olmesartan is an antihypertensive drug that acts on the angiotensin 1 (AT1 ) receptor. The present research evaluated the efficiency of Olmesartanagainst CFS.

CFS was induced by lipopolysaccharide (LPS, 1mg/kg, i.p.) once on day 1 trailed by a forced swim (10 minutes) continued for 21 consecutive times once each day. Olmesartan (1and 3mg/kg, p.o.) and dexamethasone (standard drug, 0.5mg/kg, i.p.) were given from the 1 st to 21 st day.

Immobility time was noted in the forced swim test (FST). Elevated plus maze, raised zero maze, and open field tests were employed to assess animal behavior. Plasma glucose and cortisol, lipid peroxidation, and GSH levels were determined in the whole brain. LPS and repeated forced swim sessions instigated symptoms of CFS such as memory deficit and depression and anxiety-like symptoms.

Findings suggested that Olmesartan shortened the immobility period of mice against CFS in FST. Olmesartan reduced memory deficits, increased ambulation, and exerted an anxiolytic effect. Olmesartan treatment reduced blood cortisol levels, brain TBARS, and enhanced brain GSHin the CFS mouse model.

Hence, Olmesartan may prove to be an effective treatment for CFS and related behavioral discrepancies.

Source:

Animal Models for Neuroinflammation and Potential Treatment Methods

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown etiology and without effective treatment options. The onset of ME/CFS is often associated with neuroinflammation following bacterial or viral infection.

A positron emission tomography imaging study revealed that the degree of neuroinflammation was correlated with the severity of several symptoms in patients with ME/CFS. In animal studies, lipopolysaccharide- and polyinosinic-polycytidylic acid-induced models are thought to mimic the pathological features of ME/CFS and provoke neuroinflammation, characterized by increased levels of proinflammatory cytokines and activation of microglia.

In this review, we described the anti-inflammatory effects of three compounds on neuroinflammatory responses utilizing animal models. The findings of the included studies suggest that anti-inflammatory substances may be used as effective therapies to ameliorate disease symptoms in patients with ME/CFS.

Source: Tamura Y, Yamato M, Kataoka Y. Animal Models for Neuroinflammation and Potential Treatment Methods. Front Neurol. 2022 Jun 27;13:890217. doi: 10.3389/fneur.2022.890217. PMID: 35832182; PMCID: PMC9271866. https://pubmed.ncbi.nlm.nih.gov/35832182/  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9271866/ (Full study)

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation

Summary:

COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans.
Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
Source: Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, MyoungHwa Lee, Jamie Wood, Michael R. O’Dea, Selena Dutton, Kiarash Shamardani, Kamsi Nwangwu, Rebecca Mancusi, Belgin Yalçın, Kathryn R. Taylor, Lehi AcostaAlvarez, Karen Malacon, Michael B. Keough, Lijun Ni, Pamelyn J. Woo, Daniel Contreras-Esquivel, Angus Martin Shaw Toland, Jeff R. Gehlhausen, Jon Klein, Takehiro Takahashi, Julio Silva, Benjamin Israelow, Carolina Lucas, Tianyang Mao, Mario A. Peña-Hernández, Alexandra Tabachnikova, Robert J. Homer, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Hannes Vogel, Marco M. Hefti, Daniel P. Perl, Shane Liddelow, Rebecca Folkerth, David Putrino, Avindra Nath, Akiko Iwasaki, Michelle Monje. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.  Cell (2022). Published: June 12, 2022 DOI:https://doi.org/10.1016/j.cell.2022.06.008 https://www.sciencedirect.com/science/article/pii/S0092867422007139 (Full text available as PDF file)

Electroacupuncture at BL15 attenuates chronic fatigue syndrome by downregulating iNOS/NO signaling in C57BL/6 mice

Abstract:

in English, Chinese

Chronic fatigue syndrome (CFS) has a high incidence due to the increased pressure of daily life and work in modern society. Our previous clinical studies have found the effects of electroacupuncture (EA) on CFS patients, however, the mechanism of EA on CFS is still unknown. In this study, we investigated the effects of EA on cardiac function in a CFS mouse model to explore its underlying mechanism.

The mice were randomly divided into three groups: control, CFS, and CFS mice receiving EA (CFS + EA). After behavioral assessments and echocardiographic measurement, blood and heart tissue of the mice were collected for biochemical tests, and then we evaluated the effects of EA on the CFS mouse model when nitric oxide (NO) levels were enhanced by l-arginine.

The results showed that EA ameliorated the injured motor and cardiac function. Meanwhile, EA also inhibited increased expression of inducible nitric oxide synthase (iNOS) at heart tissue and the serum NO levels in mice subjected to sustained forced swimming stress. Furthermore, the NO level in serum increased with l-arginine administration, which blocked the effects of EA on CFS mice. This study suggested that EA could improve the motor function and cardiac function in CFS mice and its effects may be associated with the down-regulation of iNOS/NO signaling.

Source: Zhu Y, Wang J, Yao L, Huang Y, Yang H, Yu X, Chen X, Chen Y. Electroacupuncture at BL15 attenuates chronic fatigue syndrome by downregulating iNOS/NO signaling in C57BL/6 mice. Anat Rec (Hoboken). 2022 May 24. doi: 10.1002/ar.24953. Epub ahead of print. PMID: 35608198. https://pubmed.ncbi.nlm.nih.gov/35608198/

Development of a Mouse Model for Chronic Fatigue Syndrome

Abstract:

The purpose of this study was to develop a clinically relevant mouse model of CFS to allow for the testing of underlying mechanisms and development of novel treatment interventions.

Mice were injected with either lipopolysaccharide (LPS) or Poly I:C systemically (0.1- 1.0 mg/kg LPS, i.p. or 0.6-6mg/kg Poly I:C) and compared to a vehicle control injection.

To test for fatigue-like behaviors, we examined voluntary wheel running (VWR) and open field activity.

To test for pain-like behaviors, muscle withdrawal thresholds (MWT) and mechanical sensitivity of the paw.

Measurements were assessed before and up to 1 week after injection of LPS or Poly I:C.

Differences in voluntary running wheel data were assessed using mixed model analysis for differences between dose, time and an interaction between dose and time.

Differences in open field parameters, MWT, and paw sensitivity between groups were assessed using repeated measures ANOVAs.

Running wheel activity was reduced after injection of either LPS or Poly I:C (χ2=15.4; p=0.003).

LPS reduced running wheel activity on days 1-3 for the 1.0 mg/kg dose of LPS and on Day 1 for Poly I:C when compared to vehicle (p<0.001).

Lower doses of LPS showed faster recovery to baseline.

For the open field testing, LPS reduced in distance travelled (F=9.1; p<0.001), increase in time standing still (F=6.5, p=0.001) but not time in center (F= 1.1, p=0.36) 24h after infection.

Post-hoc testing (Tukey’s test) showed a significant difference between the vehicle and the 1.0 mg/kg group of LPS (p=0.001).

Similar reductions were observed for the 6 mg/kg group of Poly I:C (p<0.001). For pain behaviors, there was no difference between groups in the MWT or paw sensitivity (p>0.05) for either LPS or Poly I:C.

These results show that a single injection of an infectious agent reduces physical activity and exploratory behavior, but does not produce pain behaviors.

Source: Adam Janowski, Joseph Lesnak, Ashley Plumb, Lynn Rasmussen, Kathleen Sluka. Development of a Mouse Model for Chronic Fatigue Syndrome. The Journal of Pain 23 (5): 12. https://www.sciencedirect.com/science/article/abs/pii/S152659002200092X

Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates

Abstract:

Neurological manifestations are a significant complication of coronavirus disease (COVID-19), but underlying mechanisms aren’t well understood. The development of animal models that recapitulate the neuropathological findings of autopsied brain tissue from patients who died from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are critical for elucidating the neuropathogenesis of infection and disease.

Here, we show neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis. Importantly, this is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with “long COVID”. Sparse virus is detected in brain endothelial cells but does not associate with the severity of central nervous system (CNS) injury.

We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.

Source: Rutkai I, Mayer MG, Hellmers LM, Ning B, Huang Z, Monjure CJ, Coyne C, Silvestri R, Golden N, Hensley K, Chandler K, Lehmicke G, Bix GJ, Maness NJ, Russell-Lodrigue K, Hu TY, Roy CJ, Blair RV, Bohm R, Doyle-Meyers LA, Rappaport J, Fischer T. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat Commun. 2022 Apr 1;13(1):1745. doi: 10.1038/s41467-022-29440-z. PMID: 35365631. https://www.nature.com/articles/s41467-022-29440-z (Full text)

Metabolomics study of the effect of Danggui Buxue Tang on rats with chronic fatigue syndrome

Abstract:

Danggui Buxue Tang (DBT), a traditional Chinese medicine formula for “invigorating qi and enriching blood”, has been reported to produce a good effect on chronic fatigue syndrome (CFS). However, the related mechanism remains largely unresolved. In this study, a metabolomics approach with gas chromatography coupled to mass spectrometry combined with pattern recognition was devised to estimate the extent to which DBT alleviated CFS induced by food restriction and force swimming in rats.

After four weeks of treatment, the endurance capability of rats was significantly better and the motionless time was significantly shorter in the DBT group than in CFS model group. Moreover, the activities of SOD and GSH-Px were increased, while the levels of MDA, IL-6 and TNF-α were decreased in the DBT treatment group. Fifteen significantly changed metabolites were observed in the serum of rats with CFS, which was reversed markedly by DBT treatment. Metabolic pathway analysis showed that DBT could possibly alleviate CFS in rats by regulating phenylalanine, tyrosine and tryptophan biosynthesis, glycine, serine and the metabolism of threonine, glycerolipid, glyoxylate, dicarboxylate and tyrosine. It was observed that the metabolism of glycine, serine and threonine was most closely related to the improvement of CFS by DBT treatment. This study showed that DBT could improve CFS effectively and metabolomics was a powerful means to gain insights into the traditional Chinese medicine formulas against CFS.

Source: Miao X, Li S, Xiao B, Yang J, Huang R. Metabolomics study of the effect of Danggui Buxue Tang on rats with chronic fatigue syndrome. Biomed Chromatogr. 2022 Apr 4:e5379. doi: 10.1002/bmc.5379. Epub ahead of print. PMID: 35373377.  https://pubmed.ncbi.nlm.nih.gov/35373377/

Changes in TCA cycle and TCA cycle-related metabolites in plasma upon citric acid administration in rats

Abstract:

Recent studies have reported that plasma levels of tricarboxylic acid (TCA) cycle metabolites and TCA cycle-related metabolite change in patients with chronic fatigue syndrome (CFS) and in healthy humans after exercise. Exogenous dietary citric acid has been reported to alleviate fatigue during daily activities and after exercise. However, it is unknown whether dietary citric acid affects the plasma levels of these metabolites. Therefore, the present study aimed to investigate the effects of exogenously administered citric acid on TCA cycle metabolites and TCA cycle-related metabolites in plasma.

Sprague-Dawley rats were divided into control and citric acid groups. We evaluated the effect of exogenous dietary citric acid on the plasma TCA cycle and TCA cycle-related metabolites by metabolome analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). TCA cycle metabolites, including plasma citrate, cis-aconitate, and isocitrate, were significantly elevated after exogenous administration of citric acid. Anaplerotic amino acids, which are converted to TCA cycle metabolites, such as serine, glycine, tryptophan, lysine, leucine, histidine, glutamine, arginine, isoleucine, methionine, valine, and phenylalanine, also showed significantly elevated levels.

Citric acid administration significantly increased the levels of initial TCA cycle metabolites in the plasma. This increase after administration of citric acid was shown to be opposite to the metabolic changes observed in patients with CFS. These results contribute novel insight into the fatigue alleviation mechanism of citric acid.

Source: Hara Y, Kume S, Kataoka Y, Watanabe N. Changes in TCA cycle and TCA cycle-related metabolites in plasma upon citric acid administration in rats. Heliyon. 2021 Dec 4;7(12):e08501. doi: 10.1016/j.heliyon.2021.e08501. PMID: 34934832; PMCID: PMC8654791. https://pubmed.ncbi.nlm.nih.gov/34934832/

Improvement Effects of Myelophil on Symptoms of Chronic Fatigue Syndrome in a Reserpine-Induced Mouse Model

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is associated with various symptoms, such as depression, pain, and fatigue. To date, the pathological mechanisms and therapeutics remain uncertain. The purpose of this study was to investigate the effect of myelophil (MYP), composed of Astragali Radix and Salviaemiltiorrhizae Radix, on depression, pain, and fatigue behaviors and its underlying mechanisms.

Reserpine (2 mg/kg for 10 days, intraperitoneally) induced depression, pain, and fatigue behaviors in mice. MYP treatment (100 mg/kg for 10 days, intragastrically) significantly improved depression behaviors, mechanical and thermal hypersensitivity, and fatigue behavior. MYP treatment regulated the expression of c-Fos, 5-HT1A/B receptors, and transforming growth factor β (TGF-β) in the brain, especially in the motor cortex, hippocampus, and nucleus of the solitary tract. MYP treatment decreased ionized calcium binding adapter molecule 1 (Iba1) expression in the hippocampus and increased tyrosine hydroxylase (TH) expression and the levels of dopamine and serotonin in the striatum. MYP treatment altered inflammatory and anti-oxidative-related mRNA expression in the spleen and liver.

In conclusion, MYP was effective in recovering major symptoms of ME/CFS and was associated with the regulation of dopaminergic and serotonergic pathways and TGF-β expression in the brain, as well as anti-inflammatory and anti-oxidant mechanisms in internal organs.

Source: Song JH, Won SK, Eom GH, Lee DS, Park BJ, Lee JS, Son CG, Park JY. Improvement Effects of Myelophil on Symptoms of Chronic Fatigue Syndrome in a Reserpine-Induced Mouse Model. Int J Mol Sci. 2021 Sep 22;22(19):10199. doi: 10.3390/ijms221910199. PMID: 34638540. https://pubmed.ncbi.nlm.nih.gov/34638540/

Inflammation plays a causal role in fatigue-like behavior induced by pelvic irradiation in mice

Abstract:

Fatigue is a persistent and debilitating symptom following radiation therapy for prostate cancer. However, it is not well-understood how radiation targeted to a small region of the body can lead to broad changes in behavior. In this study, we used targeted pelvic irradiation of healthy male mice to test whether inflammatory signaling mediates changes in voluntary physical activity levels.

First, we tested the relationship between radiation dose, blood cell counts, and fatigue-like behavior measured as voluntary wheel-running activity. Next, we used oral minocycline treatments to reduce inflammation and found that minocycline reduces, but does not eliminate, the fatigue-like behavioral changes induced by radiation. We also used a strain of mice lacking the MyD88 adaptor protein and found that these mice also showed less fatigue-like behavior than the wild-type controls. Finally, using serum and brain tissue samples, we determined changes in inflammatory signaling induced by irradiation in wild-type, minocycline treated, and MyD88 knockout mice.

We found that irradiation increased serum levels of IL-6, a change that was partially reversed in mice treated with minocycline or lacking MyD88. Overall, our results suggest that inflammation plays a causal role in radiation-induced fatigue and that IL-6 may be an important mediator.

Source: Wolff BS, Alshawi SA, Feng LR, Juneau PL, Saligan LN. Inflammation plays a causal role in fatigue-like behavior induced by pelvic irradiation in mice. Brain Behav Immun Health. 2021 May 19;15:100264. doi: 10.1016/j.bbih.2021.100264. PMID: 34589770; PMCID: PMC8474574. https://pubmed.ncbi.nlm.nih.gov/34589770/