Resveratrol Improves Hippocampal Atrophy in Chronic Fatigue Mice by Enhancing Neurogenesis and Inhibiting Apoptosis of Granular Cells

Abstract

Chronic fatigue is reported in more than 20% of patients examined in primary care, and this common problem affects the quality of life and work productivity.1) A large part of the chronic fatigue population meets the diagnostic criteria for chronic fatigue syndrome (CFS), which is defined by unexplained physical or mental fatigue of at least 6-month duration and a combination of nonspecific symptoms.2) Several CFS symptoms including impaired concentration, attention, and memory as well as headache suggest that the central nervous system (CNS) may be involved in CFS pathophysiology.3) Moreover, neuroimaging evidence indicates that structural and/or functional abnormalities exist in the CNS of CFS patients. For example, marked reductions in the gray matter volume are observed; 4) Cook et al. 5) found an association between subjective feelings of mental fatigue and brain responses during a fatiguing cognitive task; CFS patients always have reduced concentrations of N-acetylaspartate in the hippocampus, a putative marker of neuronal metabolism 6) ; and a 23% reduction in 5-HT 1A receptor number and affinity was found in the hippocampus of CFS patients. 7) However, neural mechanisms, especially the hippocampal substrates in CFS, are unclear in part due to the lack of a suitable animal model.In our previous study, a chronic fatigue mouse model was induced by six repeated injections of fixed killed Brucella abortus antigen solution via the tail vein every 2 weeks. 8,9) We found that brain atrophy and reduction of the hippocampal Bcl-2 and brain-derived neurotrophic factor (BDNF) mRNA expression levels were accompanied by lower spontaneous activity.8) However, the hippocampal weight was not measured in those previous studies.Resveratrol (RSV), an active component of grapevines and peanuts, is recognized as a polyphenolic activator of sirtuin 1 (Sirt1), a protein deacetylase.10) It can enhance running activity of high fat diet-fed mice two-fold by activating Sirt1. 11)Moreover, Sirt1 can protect neurons from DNA damageinduced apoptosis by downregulating p53 acetylation, an apoptotic mediator.12) RSV treatment of neural progenitor cells (NPCs) is capable of increasing differentiation and directing neurogenesis through a mechanism requiring Sirt1.13) Thus RSV may be beneficial for physical activity of our fatigue mice and even play a role in improving structural and/or functional defects of the hippocampus.We aimed to clarify the hippocampal structural and/or functional defects in this fatigue model. Another purpose of our study was to determine whether RSV intervention could improve the fatigue and reverse the abnormalities by antiapoptosis and promoting neurogenesis. MATERIALS AND METHODS Animals, Living Conditions, and Spontaneous RunningActivity Eight-week old BALB/c mice (female, 20-24 g, CLEA Japan, Tokyo, Japan) were housed singly in previously described cages 8,9) including running wheels and counters. The cages were maintained under a light-dark photoperiod (lights on from 09:00 to 17:00), and daily spontaneous ...

Resveratrol Inhibits the Proliferation of Neural Progenitor Cells and Hippocampal Neurogenesis

“…insulin sensitivity) (32), and counteract disease processes in animal models of cancers (38), cardiovascular disease (39), and some neurodegenerative conditions (40). It was also recently reported that resveratrol can promote the survival of hippocampal NPCs in an animal model of neuroinflammation (41). While resveratrol may protect neurons against oxidative and inflammatory stress, our findings suggest that in healthy mice NPCs are adversely affected by resveratrol.…”

Antidepressant-Like Effect of 1α-Hydroxyvitamin D₃ on Mice in the Forced Swimming Test

“…The expression of hippocampal brain-derived neurotrophic factor (BDNF) mRNA decreases under conditions of hippocampal atrophy (16). In addition, there is a positive association between the quantity of BDNF in the serum and cerebrocortex (17).…”

Sonic Hedgehog Signaling Mediates Resveratrol to Increase Proliferation of Neural Stem Cells After Oxygen-Glucose Deprivation/Reoxygenation Injury in Vitro

“…Resveratrol has also been shown to reduce neuronal apoptosis by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax in the hippocampus after focal cerebral ischemia in rats [12]. Moreover, resveratrol enhanced hippocampal neurogenesis and improved hippocampal atrophy in chronic fatigue mice and prenatally stressed rats [13,14]. However, the effect of resveratrol on neurogenesis after cerebral ischemic damage is largely unknown.…”