Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway

Zhu, Danshi; Zhang, Jing; Li, Guibao; Liu, Zengxun; Sun, Jinhao

doi:10.1016/j.bbrc.2015.08.005

Cited by 32 publications

(18 citation statements)

References 42 publications

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“…Therefore, owning the right compounds at appropriated doses, we tested the effects of these compounds on cell death and amount of APPs. As shown in representative micrographs of Figure 8, we observed a variety of effects, which are in line with the key role of mTOR in METH toxicity and APP stimulation [80, 94, 95]. In fact, the dose of 10 μ M METH produces roughly 35% cell death, which was totally prevented by rapamycin (100 nM).…”

Section: Resultssupporting

confidence: 72%

mTOR Modulates Methamphetamine‐Induced Toxicity through Cell Clearing Systems

Lazzeri

Biagioni

Fulceri

et al. 2018

Oxidative Medicine and Cellular Longevity

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Methamphetamine (METH) is abused worldwide, and it represents a threat for public health. METH exposure induces a variety of detrimental effects. In fact, METH produces a number of oxidative species, which lead to lipid peroxidation, protein misfolding, and nuclear damage. Cell clearing pathways such as ubiquitin-proteasome (UP) and autophagy (ATG) are involved in METH-induced oxidative damage. Although these pathways were traditionally considered to operate as separate metabolic systems, recent studies demonstrate their interconnection at the functional and biochemical level. Very recently, the convergence between UP and ATG was evidenced within a single organelle named autophagoproteasome (APP), which is suppressed by mTOR activation. In the present research study, the occurrence of APP during METH toxicity was analyzed. In fact, coimmunoprecipitation indicates a binding between LC3 and P20S particles, which also recruit p62 and alpha-synuclein. The amount of METH-induced toxicity correlates with APP levels. Specific markers for ATG and UP, such as LC3 and P20S in the cytosol, and within METH-induced vacuoles, were measured at different doses and time intervals following METH administration either alone or combined with mTOR modulators. Western blotting, coimmunoprecipitation, light microscopy, confocal microscopy, plain transmission electron microscopy, and immunogold staining were used to document the effects of mTOR modulation on METH toxicity and the merging of UP with ATG markers within APPs. METH-induced cell death is prevented by mTOR inhibition, while it is worsened by mTOR activation, which correlates with the amount of autophagoproteasomes. The present data, which apply to METH toxicity, are also relevant to provide a novel insight into cell clearing pathways to counteract several kinds of oxidative damage.

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Section: Resultssupporting

confidence: 72%

mTOR Modulates Methamphetamine‐Induced Toxicity through Cell Clearing Systems

Lazzeri

Biagioni

Fulceri

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…Our present study revealed the involvement of phosphorylation of ERK, JNK, and the p38 MAPK and PI3K/Akt pathways in microglial activation mediated by methamphetamine. These findings are consistent with the effect of methamphetamine on the activation of the MAPK and PI3K/Akt pathways in human SH-SY5Y cells 33 and PC12 cells 56 . Mounting evidence suggests that low concentrations of ROS are important for the regulation of pathways such as the TNF-ASK1 pathway 57 .…”

Section: Discussionsupporting

confidence: 89%

Molecular mechanisms underlying the involvement of the sigma-1 receptor in methamphetamine-mediated microglial polarization

Chao

Zhang

et al. 2017

Sci Rep

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Our previous study demonstrated that the sigma-1 receptor is involved in methamphetamine-induced microglial apoptosis and death; however, whether the sigma-1 receptor is involved in microglial activation as well as the molecular mechanisms underlying this process remains poorly understood. The aim of this study is to demonstrate the involvement of the sigma-1 receptor in methamphetamine-mediated microglial activation. The expression of σ-1R, iNOS, arginase and SOCS was examined by Western blot; activation of cell signaling pathways was detected by Western blot analysis. The role of σ-1R in microglial activation was further validated in C57BL/6 N WT and sigma-1 receptor knockout mice (male, 6–8 weeks) injected intraperitoneally with saline or methamphetamine (30 mg/kg) by Western blot combined with immunostaining specific for Iba-1. Treatment of cells with methamphetamine (150 μM) induced the expression of M1 markers (iNOS) with concomitant decreased the expression of M2 markers (Arginase) via its cognate sigma-1 receptor followed by ROS generation. Sequential activation of the downstream MAPK, Akt and STAT3 pathways resulted in microglial polarization. Blockade of sigma-1 receptor significantly inhibited the generation of ROS and activation of the MAPK and Akt pathways. These findings underscore the critical role of the sigma-1 receptor in methamphetamine-induced microglial activation.

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“…In this present study, we observed by immunoblotting analysis that the level of PI3K was decreased in the tBHP exposed group and it got increased in cells exposed to both tBHP and mangiferin together. To confirm that mangiferin shows its protection via the activation of PI3K, NKE cells were pretreated with the kinase inhibitor for 1 h at a concentration of 10 µM [54] , [58] , [59] , and then cells were treated with 20 μM mangiferin before tBHP exposure. After treatment, the cell viability was determined.…”

Section: Resultsmentioning

confidence: 99%

Mangiferin attenuates oxidative stress induced renal cell damage through activation of PI3K induced Akt and Nrf-2 mediated signaling pathways

Saha

Sadhukhan

Sinha

et al. 2016

Biochemistry and Biophysics Reports

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BackgroundMangiferin is a polyphenolic xanthonoid with remarkable antioxidant activity. Oxidative stress plays the key role in tert-butyl hydroperoxide (tBHP) induced renal cell damage. In this scenario, we consider mangiferin, as a safe agent in tBHP induced renal cell death and rationalize its action systematically, in normal human kidney epithelial cells (NKE).MethodsNKE cells were exposed to 20 µM mangiferin for 2 h followed by 50 µM tBHP for 18 h. The effect on endogenous ROS production, antioxidant status (antioxidant enzymes and thiols), mitochondrial membrane potential, apoptotic signaling molecules, PI3K mediated signaling cascades and cell cycle progression were examined using various biochemical assays, FACS and immunoblot analyses.ResultstBHP exposure damaged the NKE cells and decreased its viability. It also elevated the intracellular ROS and other oxidative stress-related biomarkers within the cells. However, mangiferin dose dependently, exhibited significant protection against this oxidative cellular damage. Mangiferin inhibited tBHP induced activation of different pro-apoptotic signals and thus protected the renal cells against mitochondrial permeabilization. Further, mangiferin enhanced the expression of cell proliferative signaling cascade molecules, Cyclin d1, NFκB and antioxidant molecules HO-1, SOD2, by PI3K/Akt dependent pathway. However, the inhibitor of PI3K abolished mangiferin's protective activity.ConclusionsResults show Mangiferin maintains the intracellular anti-oxidant status, induces the expression of PI3K and its downstream molecules and shields NKE cells against the tBHP induced cytotoxicity.General significanceMangiferin can be indicated as a therapeutic agent in oxidative stress-mediated renal toxicity. This protective action of mangiferin primarily attributes to its potent antioxidant and antiapoptotic nature.

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Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway

Cited by 32 publications

References 42 publications

mTOR Modulates Methamphetamine‐Induced Toxicity through Cell Clearing Systems

mTOR Modulates Methamphetamine‐Induced Toxicity through Cell Clearing Systems

Molecular mechanisms underlying the involvement of the sigma-1 receptor in methamphetamine-mediated microglial polarization

Mangiferin attenuates oxidative stress induced renal cell damage through activation of PI3K induced Akt and Nrf-2 mediated signaling pathways

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