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.
Highlights
Methamphetamine (METH) is a commonly abused drug that may result in neurotoxic effects
asiatic acid (AA) significantly increased the viability of 1 mM METHstimulated SH-SY5Y cells in a concentration-dependent manner compared to that of cells treated with 1 mM METH alone (Additional file 1: Figure S1c)
Our findings show that AA has a protective role against METH-induced neuroinflammation and neurotoxicity, through inhibition of the NF-kB/STAT3/extracellular signal-regulated kinase (ERK) and mitochondria-mediated apoptosis pathway
Summary
Methamphetamine (METH) is a commonly abused drug that may result in neurotoxic effects, which contribute to neuronal damage and inflammation [1, 2]. It has been well-recognized that high doses of METH impair nigrostriatal dopaminergic systems in both rodents [3] and primates [4]. METH may act upon neurons as a central processor of inflammation by releasing pro-inflammatory molecules [9] These pro-inflammatory molecules may further activate downstream apoptotic signaling pathways in neurons, resulting in neuronal death and/or the activation of glial cells, which can further exacerbate neuroinflammation. The pathogenesis of dopaminergic neurotoxicity observed in Parkinson’s disease (PD) is similar to the neuroinflammatory and neurotoxic effect of METH [10]
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