Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines

Abstract

-Methamphetamine (METH) is a neurotoxic drug that causes brain damage by inducing neuronal and glial cell death together with glial cell hyperactivity-mediated progressive neurodegeneration. Previous studies have shown that METH induced glial cell hyperactivity and death via oxidative stress, the inflammatory response, and endoplasmic reticulum stress (ER stress) mechanisms, and melatonin could reverse these effects. However, the exact mechanism of the protective role of melatonin in METH-mediated ER stress has not been understood. This study investigated the protective effect of melatonin against METH toxicity-mediated ER stress in glial cells. Our study demonstrated that METH increased glial cell toxicity related to METH-induced ER stress by stimulating the unfolded protein response (UPR) to activate the expression of ER stress transducers, including phosphorylated doublestranded RNA-activated protein kinase (PKR)-like ER kinase (p-PERK), activating transcription factor (ATF6), and phosphorylated inositol-requiring enzyme 1 (p-IRE1). Moreover, the expression of binding immunoglobulin protein (Bip), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, phosphorylated eukaryotic translation initiation factor 2 alpha (p-eIF2α) and spliced X-box-binding protein-1 (XBP-1) mRNA were also increased. Melatonin reduced ER stress induced by METH toxicity by reducing the expression of ER stress response genes and proteins in a concentration-dependent manner. In addition, melatonin promoted the expression of Bip chaperone in a concentration-dependent manner. Taken together, our findings suggest that melatonin can protect against ER stress-induced glial cell death induced by METH.

ERN1 modifies the effect of glutamine deprivation on tumor growth related factors expression in U87 glioma cells

“…8. Glutamine withdrawal down-regulated the expression of most studied factors and these results completely agree with functional activity of ATF6, EIF2AK3/PERK, GLO1, BIRC5/survivin, and RAB5C proteins, which shown pro-proliferative effects [16][17][18][24][25][26][27][28][29][30][31][32].…”

“…However, the regulation of the expression of many other tumor growth related genes by glutamine deprivation in relation to inhibition of ERN1 to not to be clarified yet. Among them AtF6 (activating transcription factor 6) gene encoding an important transcription factor, which participate in the endoplasmic reticulum stress signaling and controls the transcription of numerous stress responsible genes [24,25]. Furthermore, ATF6 activates stress responsible gene expressions and regulates cellular senescence, which is known as an anti-tumor barrier [5,26].…”

“…Our results agree with data Hutschenreuther et al [33] that glutamine withdrawal decreases GLO1. Recently was shown that the expression of GLO1 is increased in some cancers and plays a pro-tumor role, participates in epithelial-to-mesenchymal transition, transformation into a neoplastic-like phenotype [25,34]. This enzyme metabolizes methylglyoxal, a cytotoxic metabolite, which induces the formation of advanced glycation of end-products and is increased in cancer [26].…”

Methamphetamine exposure triggers apoptosis and autophagy in neuronal cells by activating the C/EBPβ‐related signaling pathway

“…Our previous study (25) together with others' works (26,27) showed that Meth is able to induce autophagy in dopaminergic neurons. In recent years, emerging data showed that Meth is a strong inducer of ER (endoplasmic reticulum) stress (28)(29)(30)(31). However, the relationship between Meth-induced ER stress and autophagy is unclear.…”

Celastrol ameliorates endoplasmic stress-mediated apoptosis of osteoarthritis via regulating ATF-6/CHOP signalling pathway

“…[ 24 ] It was reported to have a strong pharmacological activity on regulating miR‐223 and SDF‐1/CXCR4 signalling pathway in OA. [ 25,26 ] We used a Tm‐exposed chondrocyte OA model, and we confirmed the protective effects of celastrol on Tm‐exposed chondrocytes, which occurred through two mechanisms, namely, enhancement of cell viability and reduction in cell apoptosis. Celastrol suppressed the apoptosis rate and down‐regulated the expressions of caspase‐3, caspase‐6 and caspase‐9 in supernatant and intracellular of Tm‐exposed chondrocytes.…”