Abstract
Elephantopus scaber L. (family: Asteraceae) has been traditionally utilized as a folkloric medicine and scientifically shown to exhibit anti-inflammatory activities in various in vivo inflammatory models. Given the lack of study on the effect of E. scaber in neuroinflammation, this study aimed to investigate the anti-neuroinflammatory effect and the underlying mechanisms of ethyl acetate fraction from the leaves of E. scaber (ESEAF) on the release of pro-inflammatory mediators in lipopolysaccharide (LPS)-induced microglia cells (BV-2). Present findings showed that ESEAF markedly attenuated the translocation of NF-κB to nucleus concomitantly with the significant mitigation on the LPS-induced production of NO, iNOS, COX-2, PGE2, IL-1β, and TNF-α. These inflammatory responses were reduced via the inhibition of p38. Besides, ESEAF was shown to possess antioxidant activities evident by the DPPH and SOD scavenging activities. The intracellular catalase enzyme activity was enhanced by ESEAF in the LPS-stimulated BV-2 cells. Furthermore, the formation of ROS induced by LPS in BV-2 cells was reduced upon the exposure to ESEAF. Intriguingly, the reduction of ROS was found in concerted with the activation of Nrf2 and HO-1. It is conceivable that the activation promotes the scavenging power of antioxidant enzymes as well as to ameliorate the inflammatory response in LPS-stimulated BV-2 cells. Finally, the safety profile analysis through oral administration of ESEAF at 2000 mg/kg did not result in any mortalities, adverse effects nor histopathologic abnormalities of organs in mice. Taken altogether, the cumulative findings suggested that ESEAF holds the potential to develop as nutraceutical for the intervention of neuroinflammatory disorders.
Highlights
Inflammation as one of the defense responses to eliminate deleterious agents or injured tissues in order to maintain the homeostasis, prevents continued tissue damage and restores normal function (Medzhitov, 2008)
ESEAF in LPS-stimulated BV-2 cells. (B) The bar chart demonstrated the production of prostaglandin E2 (PGE2) after pretreatment of ESEAF on LPS-stimulated BV-2 cells. (C) Western blot analysis on the inhibitory effect of ESEAF in LPS-induced inducible nitric oxide synthase (iNOS), COX-2, p38, and phospho-p38 in BV-2 cells. β-actin was utilized as a loading control for all experiments. (D) The relative protein expression of iNOS, COX-2, and p-p38/p38
Attenuation of reactive oxygen species (ROS) generation in microglia cells becomes a common therapeutic target for neuroinflammation-related diseases. Consistent with this notion, our results revealed that ESEAF efficiently reversed the production of ROS in LPS-induced BV-2 cells when compared to the LPS alone which caused a significant accumulation of ROS
Summary
Inflammation as one of the defense responses to eliminate deleterious agents or injured tissues in order to maintain the homeostasis, prevents continued tissue damage and restores normal function (Medzhitov, 2008). The resident immune cells of central nervous system, become activated upon the initiation of inflammatory responses that induces detrimental neurotoxic. When activated microglia undergo a prolonged inflammation triggered by a plethora of stimuli could induce neuronal damage to neighboring neurons and leading to various neurodegenerative diseases including multiple sclerosis, Alzheimer’s disease (AD), and Parkinson’s disease (Block and Hong, 2005). Suppression of the inflammatory mediators by activated microglia could provide a therapeutic target for neuroinflammatory diseases. Upon the stimulation of lipopolysaccharide (LPS), NF-κB translocate to the nucleus further transcribing several pro-inflammatory genes including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) (Surh et al, 2001; Ghosh and Karin, 2002). NF-κB exacerbated and amplified the inflammatory responses by increasing pro-inflammatory mediators including iNOS, COX-2, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Targeting NF-κB and p38 has become another therapeutic approach to rescue the neurons from death as well to mitigate the progression of neurodegenerative diseases
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