Mood Symptoms And Chronic Fatigue Syndrome Due To Relapsing-Remitting Multiple Sclerosis Are Associated With Immune Activation And Aberrations in The Erythron Part 3
Aug 16, 2023
4.3. Fatigue and PP due to MS and the Erythron
The third major finding of the present study is that chronic fatigue and affective symptoms due to MS, but not MS per se, are associated with deficits in the erythron, namely, lowered numbers of RBCs, Hct, and Hb, whereas alterations in RBC indices have less impact. Thus, aberrations in RBC indices (especially increased RDW) are a hallmark of MS, but not chronic fatigue and affective symptoms due to MS. Our findings extend previous results showing that the erythron profile of MS patients indicates altered RDW values [92] and that, in MS, there is a significant association between high RDW and EDSS scores [93]. Other hemorheological features of MS comprise an increased aggregation of RBCs due to increased peripheral inflammation [92]. RBC numbers, Hb, and Hct may differ significantly between RRMS and SPMS and are lower in RRMS compared to normal controls [35]. Furthermore, major depression is associated with abnormal erythroid parameters including decreased RBCs, Hct, and Hb, probably as a consequence of the chronic mild inflammatory response during that illness [36,37]. In chronic fatigue syndrome, RBCs are less deformable and show lower membrane fluidity and zeta-surface charge compared with RBCs of healthy controls [94]. It is common knowledge that anemia and iron deficiency may cause chronic fatigue symptoms.
Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.
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Our results suggest that aberrations in the erythrina in MS may contribute to the pathophysiology of chronic fatigue and affective symptoms due to MS. First, disorders in the erythrina resulting from activated IRS may induce the hypoxia-inducible factor (HIF) pathway leading to hypoxic damage [95] as repeatedly reported in fatigue, depression, and anxiety [96]. Second, RBCs have important antioxidant defenses including superoxide dismutase, catalase, and glutathione peroxidase activities [97], whilst hemoglobin may also serve as an antioxidant [97]. Increased lipid peroxidation, which accompanies IRS activation [98], may suppress the antioxidant defenses in the RBCs and change the morphometric features of RBCs and functions of Hb, whilst these changes may be attenuated by the administration of antioxidants [99]. Moreover, the antioxidant capacity of RBCs is reduced in MS leading to increased oxidative stress [92], which plays a key role in chronic fatigue syndrome and affective symptoms [16,98]. Thus, disturbances in RBCs and their antioxidant capacity coupled with high peripheral oxidative stress and changes in blood rheology may increase the vulnerability to oxidative damage and contribute to ischaemic tissue damage [92] and, therefore, to chronic fatigue and affective symptoms.
5. Limitations
First, the results would have been more informative if we had assessed biomarkers of oxidative stress including lipid peroxidation and RBC superoxide dismutase, autoimmune biomarkers, and neurotoxic tryptophan catabolites, which are induced during immune activation. Second, although this study was performed on a smaller study sample, the sample size was estimated a priori, based on a power of 0.8. Moreover, post hoc computation of the achieved power, given the computed effect and sample sizes and alpha, show that the power of the regression analyses shown in Table 4 ranges between 0.92 and 1.0. Third, future research should examine the differences in immune and erythrina profiles between the remission and acute relapse phases of RRMS and examine whether RRMS patients with increased immune activation show a higher relapse rate or an earlier relapse compared with RRMS patients without immune activation.
6. Conclusions
A considerable proportion of RRMS patients in remission exhibit active immune-inflammatory pathways and neuroimmune toxicity. Activated immune-inflammatory responses and an aberrant erythrina may explain the presence of chronic fatigue, affective symptoms, psychosomatic symptoms, insomnia, and autonomic symptoms throughout the remission period of RRMS. MS-related chronic fatigue and affective symptoms are caused by immunological activation and erythrocyte abnormalities. The more generalized IRS and CIRS activation, as well as the Th1 profile and Th17-axis, are therapeutic targets to prevent subsequent relapses in a subset of remitted RRMS patients. Erythron abnormalities are emerging therapeutic targets for the treatment of RRMS-related chronic fatigue, and psychosomatic and mood symptoms.
Author Contributions: A.A.A.A., A.-K.K.A.J., and H.K.H. recruited the patients and performed the sampling. The measurements of serum biomarkers were performed by A.F.A., C.T., and H.K.A.-H. The study design and statistical analysis were carried out by M.M., A.F.A., and M.M. wrote and edited the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: The study was funded by the C2F program of Chulalongkorn University, Thailand. Grant Number: 64.310/436/2565.
Institutional Review Board Statement: The approval to conduct the current study was obtained from the institutional ethics board of the College of Medical Technology, The Islamic University of Najaf, Iraq (doc. no 11/2021). In this study, we also followed Iraqi and foreign ethics and privacy rules based on the guidelines of the World Medical Association Declaration of Helsinki, the Belmont Report, CIOMS guidelines, and the International Conference on Harmonization of Good Clinical Practice. Our IRB adheres to the International Guideline for Human Research Safety (ICH-GCP).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish this paper.
Data Availability Statement: After the authors have thoroughly utilized the dataset, the corresponding author (M.M.) will make all pertinent data available upon reasonable request.
Acknowledgments: We would like to express our appreciation to the individuals who worked diligently to compile the data at the Neuroscience Center of Al-Sader Medical City of Najaf, Iraq.
Conflicts of Interest: The authors have no conflict of interest associated with the submitted article.
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