Possible role of oxidative stress and immunological activation in mouse model of chronic fatigue syndrome and its attenuation by olive extract

Abstract

Various putative theories involved in the development of chronic fatigue syndrome revolve around the role of stress, infection and oxidative stress. Scientific evidence highlighting the protective role of nutritional supplements in chronic fatigue syndrome is lacking. Based on these assumptions, the present study was designed to evaluate the effect of olive extract in a mouse model of immunologically-induced fatigue, wherein purified lipopolysaccharide (LPS) and Brucella abortus (BA) antigen were used as immunogens. The assessment of chronic fatigue syndrome was based on immobility period during chronic water-immersion stress test for 10 min daily. The stress-induced hyperalgesia was measured by tail withdrawal latency. Mice challenged with LPS or BA for 19 days showed significant increase in the immobility time, hyperalgesia and oxidative stress on the 19th day. Serum tumor necrosis factor-alpha (TNF-α) levels were also markedly increased with LPS or BA challenge. Concurrent treatment with olive extract resulted in a significant decrease in the immobility time as well as hyperalgesia. There was significant attenuation of oxidative stress as well as serum TNF-α levels. The results of the present study strongly indicate the role of oxidative stress and immunological activation in the pathophysiology of chronic fatigue syndrome and highlight the valuable role of olive extract in combating chronic fatigue syndrome.

Introduction

Chronic fatigue syndrome is characterized by debilitating fatigue, complicated by various physical and mental symptoms as a result of biochemical or immunological disturbances (Fukuda et al., 1994, Reeves et al., 2005). Due to its obscure and multifactorial etiology, it is difficult to diagnose and treat chronic fatigue syndrome. Major contributors in the development of chronic fatigue syndrome include physical stress, infection and imbalance in the antioxidant pool (Behan & Behan, 1988, Demitrack et al., 1991, Klimas & Koneru, 2007). In the light of ongoing research on chronic fatigue syndrome, it is speculated that a specific bacterial or viral infection and immune dysfunction act as potential stressors that result in the production of reactive oxygen species (ROS) such as superoxide ions, peroxides and nitric oxide (Gaab et al., 2005, Klimas & Koneru, 2007). Elevated level of prooxidants such as superoxide anion, nitric oxide and peroxynitrite results in the impairment of normal integrity and physiology of cellular function (Gaab et al., 2005, Pall & Satterlee, 2001). These intermediates mediate a large number of cytotoxic mechanisms such as lipid peroxidation, mitochondrial dysfunction and hence result in cellular injury and death (Yoshikawa et al., 1994).

Earlier clinical and experimental studies have highlighted the interaction of immunologic challenge and development of chronic fatigue syndrome (Chao et al., 1992). Immunogens such as lipopolysaccharide (LPS) endotoxin or Brucella abortus (BA) have been commonly implicated antigens in chronic fatigue syndrome (Gaab et al., 2005, Chao et al., 1992, Ottenweller et al., 1998). Antigens such as LPS or BA interact with the cellular system and stimulate the generation of reactive oxygen species such as superoxide anions, hydroxyl radicals and peroxynitrite formation as well as release of pro-inflammatory cytokines (Gaab et al., 2005, Sakaguchi & Furusawa, 2006, Sugino et al., 1987, Svetic et al., 1993). In order to attenuate the disabling mechanisms of chronic fatigue syndrome, nutritional supplements with potent antioxidant activity as well as dietary modification can be beneficial. Various in-vivo studies have been done where researchers have shown the beneficial effects of herbal products in animal models of chronic fatigue (Chen et al., 2008, Logan & Wong, 2001, Singal et al., 2005).

Prolivols, the natural byproduct of olive oil processing, are aqueous extracts of the olive fruit. Prolivols are rich in polyphenols as well as ‘hydroxytyrosol’, the main chemical constituent of prolivols (Schaffer et al., 2007, Visioli et al., 2000a). Numerous studies have been carried out on hydroxytyrosol, demonstrating their potential antioxidant properties (Goya et al., 2007, Maiuri et al., 2005, Rietjens et al., 2007, Visioli et al., 2000b). Our laboratory has earlier demonstrated the potential antioxidant properties of natural polyphenols such as curcumin and naringin in experimental model of chronic fatigue syndrome (Gupta et al., 2009, Vij et al., 2009).

In light of the above evidence, the present study was designed to evaluate the effect of prolivols, an olive fruit extract, in LPS- or BA-induced fatigue in a murine model of water-immersion stress.