Dopaminergic neurons are vulnerable to oxidative products

Dopaminergic neurons are vulnerable to oxidative products and inflammatory responses; these processes may play important roles in the etiology of PD. Because glial sphk are the main generators of inflammatory responses in the CNS, the possibility that PD results from glial cell dysfunction must be considered [31]. Reactive astrocytes are abundant in the SNs of PD cases and in the 6-hydroxydopamine and MPTP PD animal models [31–33]. Astrocytes normally exert neuroprotective functions; however, they may contribute to harmful chronic inflammation under adverse stimulation [31]. To date, the roles that astrocytes play in various parkinsonian syndromes are not sufficiently understood because astroglial reactions occur in late-stage disease and therefore do not directly participate in initiating cell death [34]. Our results showed that AP-1 expression significantly increased in astrocytes in MPTP-treated mice. This result suggests that astroglial AP-1 can stimulate sterile inflammation in PD. Furthermore, AP-1 expression was decreased in GFAP-positive astrocytes in the SNs of TLR4-deficient mice, suggesting that TLR4 signaling mediated the astroglial activation of AP-1 and enhanced neuronal cell death.
Disclosure
Introduction Lysimachia foenum-graecum extract (LFE) is used as a traditional oriental medicine to treat colds, rheumatism, headache, toothache, and digestive dysfunctions (Li et al., 2009, Shen et al., 2005). In terms of the active components responsible for these wide ranging pharmacological properties, one of its triterpene glycosides, foenumoside E, has been reported to have anti-inflammatory effects (Li et al., 2009). Recently, LFE was found to have anti-adipogenic effects by high throughput screening of a natural product extract library, and foenumoside B (FSB) was found to be the active component responsible for the inhibitory effects of LFE during adipocyte differentiation (Seo et al., 2011). However, the effect of FSB on LPS-induced inflammatory response has not been previously studied. The inflammatory response is mediated by the activations of various immune cells, such as, macrophages and monocytes. In particular, macrophages play an important role in regulating immune response to invading pathogens via phagocytosis and cytokine secretion. However, the excessive and chronic activation of macrophages leads to systemic inflammatory diseases, such as, rheumatoid arthritis, asthma, Alzheimer's disease and sepsis (Tracey, 2002). Therefore, the suppression of activated macrophages is viewed as a valuable strategy for the treatments of inflammatory diseases. Lipopolysaccharide (LPS) is a primary component of endotoxin from Gram negative bacterial cell walls, and recent studies have demonstrated LPS exists in mammalian GI tract and suggested that it possibly acts as an in vivo inflammatory stimulator (Lin et al., 2008, Sanlioglu et al., 2001). Several pro-inflammatory mediators, that is, nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) are secreted by LPS-activated macrophages (Hu et al., 2014). These macrophages subsequently induce the activations of toll-like receptor 4 (TLR4)-mediated intracellular signaling cascades (e.g., nuclear factor-κB (NF-κB) and activator protein-1 (AP-1)), signal transducers and activators of transcription (STATs), phosphoinositide-3 kinase/AKT(PI3K/AKT) and mitogen-activated protein kinases (MAPKs) (Chun et al., 2012, Shin et al., 2010). In particular, NF-κB and AP-1 are pivotal transcription factors that play key roles in the expressions of inflammatory genes (Lappas et al., 2002, Li and Verma, 2002). Upon stimulation with LPS, the activations of STATs, AKT, and MAPKs mediate signaling cascades leading to the activations of NF-κB and AP-1 in activated macrophages (Guha and Mackman, 2001, Kaminska, 2005), which also coordinate the inductions of a variety of inflammatory proteins (Karin and Ben-Neriah, 2000).