Molecular and Neuronal Mechanisms of Chronic Fatigue Syndrome: From Bench to Bedside

Abstract

Fatigue is one of the symptoms produced by our bioalarm system. However, we may not have paid enough attention to the importance of fatigue, since fatigue normally disappears after rest or sleeping overnight. It has been recognized that patients with chronic fatigue syndrome (CFS), showing debilitating and long-lasting fatigue which is not relieved by rest, has been producing a huge amount of economic loss in our modern society. The CFS is characterized by not only severe fatigue, but also the impairment of neuroendocrine, autonomic, cognitive and immune functions, suggesting a diturbance in the neuronal-endocrine-immune interactions. One of the reasons for not having a specific medicine may be because of the unknown etiology of this syndrome. Clinical symptoms have suggested an association of viral infection with the cause of CFS. Although researchers have not identified the specific pathogen yet, many possible viruses have been reported to induce CFS. In this special issue co-organized by Dr. Yosky Kataoka (RIKEN, Kobe, Japan) and me, we present recent findings on molecular and neuronal mechanisms of CFS using animal models and human patients. It is well known that chronic stress is deeply associated with the onset or exacerbation of CFS. Ogawa et al. demonstrated that rats given a sleep-depriving continuous stress showed morphologically atrophic and functionally suppressed somatotrophs as well as hyperactive melanotrophs including secretion of -MSH (see the chapter by Ogawa et al.). They also suggested that the serum level of -MSH can be a bio-marker for CFS at the early stage. Transforming growth factor(TGF) was also suggested as a possible bio-marker for CFS. TGFwas identified from cerebrospinal fluid in physically exhausted rats, which was found to induce fatigue when administered to normal rats. Those findings in the animal models have been supported by the clinical study showing an elevation of active TGFin the serum of CFS patients (see the chapter by Inoue). Neuroinflammation is characterized by activation of glial cells secreting cytokines, chemokines, radicals, growth factors and proteases in the central nervous system (CNS). It has been indicated that neuroinflammation plays an important role in various neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases and it is likely that CFS also involves neuroinflammation. Kataoka et al. showed presence of neuroinflammation using positron emission tomography (PET) during central fatigue, which was induced by excessive stimulation with cortical spreading depression of the brain. They also demonstrated that central fatigue induced by systemic injection of synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly I:C), was suppressed by minocycline (an inhibitor of microglial activation). In this immunologically induced fatigue model, it is suggested that the balance of interleuikin1 (IL-1 ) and its intrinsic antagonist, IL-1 receptor antagonist, is important for the induction and prolongation of fatigue (see the chapter by Kataoka et al.). Ifuku et al. also demonstrated that the activation of microglia in the hypothalamus, which was evoked by systemic poly I:C injection and was accompanied by the enhanced expression of microglial IL-1 , was involved in the onset of the immunologically induced fatigue (see the chapter by Ifuku et al.).