Ursolic acid attenuates lipopolysaccharide-induced cognitive deficits in mouse brain through suppressing p38/NF-κB mediated inflammatory pathways
Highlights
► Ursolic acid (UA) is a plant-derived pentacyclic triterpenoid. ► UA is reported to possess multiple biological functions. ► Our findings indicate that UA may protect against LPS-induced cognitive deficits. ► Effects of UA are mediated by blocking p38 MAPK and NF-κB signaling activation. ► These data suggest that UA could be recommended as an anti-brain inflammation agent.
Introduction
Systemic administration of lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, is a primary mediator of inflammatory damage. It may cause brain inflammatory responses and result in cognitive deficits, which might increase the risk of major depressive episodes. Toll-like receptor-4 (TLR4), which is necessary for signal transduction induced by LPS, will be up-regulated in LPS-treated mouse brain (Chakravarty & Herkenham, 2005). TLR4 shares the capacity to bind the intracellular myeloid differentiation factor 88 (MyD88) (Kawai et al., 2001, Shen et al., 2008). This interaction of TLR4 with MyD88 initiates a complex signaling pathway, including the activation of mitogen-activated protein kinases (MAPKs), Akt and inhibitory κB (IκB). These changes finally lead to the activation of nuclear factor-kappa B (NF-κB) which is responsible for the induction of various inflammatory molecules including COX-2, iNOS, TNF-α, IL-1β, IL-2 and IL-6 (An et al., 2002, Cruz et al., 2001, Guha and Mackman, 2002, Patel and Corbett, 2004). The increased inflammatory agents may lead to a collection of behavioral changes (Dunn & Swiergiel, 2005), produce alterations in cognitive processes (Sparkman, Martin, Calvert, & Boehm, 2005) and cause inflammatory brain diseases. Therefore, inhibition of the release of pro-inflammatory factors is an important approach to prevent inflammation-associated cognitive deficits.
Ursolic acid (UA: 3β-hydroxy-urs-12-en-28-oic acid), a pentacyclic triterpenoid derived from berries, leaves, flowers, fruits and many kinds of medicinal plants, has a wide range of biological activities such as antioxidant (Kim et al., 1996), anti-inflammatory (Ovesna, Vachalkova, Horvathova, & Tothova, 2004), anti-tumor (Shishodia, Majumdar, Banerjee, & Aggarwal, 2003), hepatoprotective (Liu, 1995) and immunoregulatory effects (Raphael & Kuttan, 2003). Shih et al. reported that UA exerts protective effect on the hippocampal neurons against kainate-induced excitotoxicity in rats, at least in part, through free radical scavenging (Shih, Chein, Wang, & Fu, 2004). Recently, Lu et al. indicated that UA could protect mice against d-gal-induced brain inflammation (Lu et al., 2007). However, there is no report in the literature of studies designed to investigate whether UA has an effect against LPS-induced neuroinflammation and cognitive deficits in mice. In the present study, we addressed this question and investigated the potential mechanism underlying its action.
Section snippets
Subjects
Male C57BL/6 mice (22 ± 1 g) were purchased from the Shanghai SLAC Laboratory Animal Ltd (Shanghai, China). Before experiments, the mice had free access to food and water and were kept under constant conditions of temperature (23 ± 1 °C) and humidity (60%). Four mice were housed per cage on a 12 h light/12 h dark schedule (lights on 08:30–20:30). After acclimatization to the laboratory conditions, mice were randomly divided into six groups: two groups of mice received UA in distilled water containing
Effect of UA on the body weight of LPS-treated mice
The body weights of mice in each group were also evaluated at the 5th and the 13th weeks. At the 5th week, there was no significant difference among the six group [F(5, 36) = 0.266, p > 0.05] (Fig. 2). After 8 weeks of LPS injection, mice suffered significant weight loss [F(5, 36) = 11.356, p < 0.001]. Interestingly, the body weight of LPS-treated mice received daily 10 or 20 mg/(kg day) UA was higher than that of mice treated with LPS alone. Especially, no significant difference of body weight between
Discussion
UA is a pentacyclic triterpene acid naturally occurring in a number of foods and medicinal plants. Evidence shows that it has many biological functions, such as anti-cancer and anti-inflammatory activities (Huang et al., 1994, Máñez et al., 1997, Ren et al., 2005). Previous evidence demonstrated that UA suppressed phorbol 12-myristate13-acetate (PMA)-mediated inflammation by inhibiting the PKC signal transduction pathway (Subbaramaiah, Michaluart, Sporn, & Dannenberg, 2000). Recent report from
Conflict of interest
All authors have no conflicts of interest.
Acknowledgments
This work is supported by A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), by the 2010 “Qinglan Project” Scientific and Technological Innovation Team Training Program of Jiangsu College and University, grants from the Natural Science Foundation for Colleges and Universities in Jiangsu Province (09KJB180009), by the National Natural Science Foundation of China (30950031), by the Major Fundamental Research Program of Natural Science
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These authors contributed equally to this work.