Asiatic acid attenuates methamphetamine-induced neuroinflammation and neurotoxicity through blocking of NF-kB/STAT3/ERK and mitochondria-mediated apoptosis pathway

Abstract

BackgroundMethamphetamine (METH) is a commonly abused drug that may result in neurotoxic effects. Recent studies have suggested that involvement of neuroinflammatory processes in brain dysfunction is induced by misuse of this drug. However, the mechanism underlying METH-induced inflammation and neurotoxicity in neurons is still unclear. In this study, we investigated whether asiatic acid (AA) effected METH-mediated neuroinflammation and neurotoxicity in dopaminergic neuronal cells. And we further determined whether the effect involved in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK) pathway.MethodsWe used the human dopaminergic neuroblastoma SH-SY5Y cell line, murine microglial BV2 cell line, and primary culture of rat embryo mesencephalic neurons. Pro-inflammatory cytokine production was monitored by ELISA and RT/real-time PCR. The cell cycle distribution and mitochondrial membrane integrity was analyzed by flow cytometry. We used immunoblotting, DNA-binding activity, and immunofluorescence staining to analyze the effect of AA on activation of the NF-κB, STAT3, MAPK-ERK, and apoptosis signaling pathways.ResultsMETH induced TNF receptor (TNFR) expression and led to morphological changes of cells. Additionally, this drug increased pro-inflammatory cytokine (TNFα and IL-6) expression. AA significantly suppressed METH-induced TNFR expression in concentration dependent. Increased secretion of TNFα and IL-6 was inhibited in METH-stimulated neuronal cells by AA administration. AA showed significant protection against METH-induced translocation of NF-κB/STAT3 and ERK phosphorylation. AA inhibited METH-induced proteolytic fragmentation of caspase-3 and PARP. The pro-apoptotic protein Bax was significantly decreased, while the anti-apoptotic protein Bcl-xL was increased by AA treatment in METH-stimulated cells. A similar protective effect of AA on mitochondrial membrane integrity was also confirmed by flow cytometry and immunofluorescence staining.ConclusionsBased on the literatures and our findings, AA is a promising candidate for an anti-neurotoxic agent, and it can potentially be used for the prevention and treatment of various neurological disorders.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1009-0) contains supplementary material, which is available to authorized users.

Asiatic Acid, Corosolic Acid, and Maslinic Acid Interfere with Intracellular Trafficking and <i>N</i>-Linked Glycosylation of Intercellular Adhesion Molecule-1

“…Previous studies reported that asiatic acid inhibited the NF-κB signaling pathway in various types of cells. [35][36][37][38][39][40] Asiatic acid was found to decrease TNF-α-induced ICAM-1 expression. 41) Thus, asiatic acid appears to exert a slight effect on the IL-1α-induced ICAM-1 transcription, at least in A549 cells, and it may rather have affected translation or post-translational processes in order to up-regulate ICAM-1 protein levels.…”

Helicobacter hepaticus infection induces chronic hepatitis and fibrosis in male BALB/c mice via the activation of NF‐κB, Stat3, and MAPK signaling pathways

“…The Jak‐Stat and NF‐κB pathways regulate inflammatory response and play key roles in the development of inflammation . NF‐κB and Stat3 activation is also known to be a regulatory mechanism for expressing Tnf‐α and Il‐6 . To determine whether H hepaticus ‐induced inflammatory liver pathology is linked to activation of the NF‐κB and Jak‐Stat signaling pathways, levels of the phosphorylated p65 and Stat3 were examined in the liver of H hepaticus ‐infected mice at 8, 12, 16, 20, and 24 WPI using Western blotting.…”

“…activation is also known to be a regulatory mechanism for expressing Tnf-α and Il-6. 24 To determine whether H hepaticus-induced inflammatory liver pathology is linked to activation of the NF-κB and Jak-Stat signaling pathways, levels of the phosphorylated p65 and Stat3 were examined in the liver of H hepaticus-infected mice at 8, 12, 16, 20, and 24 WPI using Western blotting. The phosphorylation of both p65 and Stat3 was significantly increased in the H hepaticus-infected mice compared to the controls at all time points ( Figure 6A and B).…”

Asiatic Acid Inhibits OVX-Induced Osteoporosis and Osteoclastogenesis Via Regulating RANKL-Mediated NF-κb and Nfatc1 Signaling Pathways

“…containing the main component asiatic acid has been prevalently used in treating acute or chronic inflammation of human organ systems in many ancient Asian countries, including China, Japan and Korea. Recently, asiatic acid has been found to display suppressive effects on cancer cells, inflammation, and cardiac hypertrophy (Chen et al, 2014;Xu et al, 2015;Park et al, 2017). Particularly, asiatic acid was able to modulate the NF-kB related signaling pathway in neuroinflammation (Park et al, 2017;Qian et al, 2018).…”

“…Asiatic acid also reduces the proliferation of human ovarian cancer cells by blocking the activation of the PI3K/Akt/mTOR pathway, as well as the proliferation of HepG2 cells by inhibiting the expression NDR1/2 kinase and enhancing the stability of p21WAF1/CIP1 protein (Chen et al, 2014;Ren et al, 2016). Furthermore, recent studies demonstrate that asiatic acid can attenuate neuroinflammation induced by various toxic agents via regulating Sirt1/NF-kB or NF-kB/STAT3/ERK signaling pathways (Park et al, 2017;Qian et al, 2018). Asiatic acid is also found to be effective in the treatment of cardiac hypertrophy through IL-1b-activated NF-kB signalling (Xu et al, 2015).…”