Taurine inhibits 2,5-hexanedione-induced oxidative stress and mitochondria-dependent apoptosis in PC12 cells

Li, Shuangyue; Guan, Huai; Qian, Zhiqiang; Sun, Yijie; Gao, Chenxue; Li, Guixin; Yang, Yi; Piao, Fengyuan; Hu, Shuhai

doi:10.2486/indhealth.2016-0044

Cited by 26 publications

(12 citation statements)

References 31 publications

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“…Other studies have shown that ethanol exposure results in a significant reduction of NGF expression in the hippocampus and cortex in male mice [32]. While NGF expression can also be reduced through chronic exposure to amphetamine in the same areas [33]. These results indicate that NGF is a potential target for the toxic interference mediated by certain neurotoxicants.…”

Section: Introductionmentioning

confidence: 82%

2,5-Hexanedione mediates neuronal apoptosis through suppression of NGF via PI3K/Akt signaling in the rat sciatic nerve

et al. 2019

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Because precise mechanism for 2,5-hexanedione (HD)-induced neuronal apoptosis largely remains unknown, we explored the potential mechanisms both in vivo and in vitro. Rats were intraperitoneally exposed to HD at different doses for 5 weeks, following which the expression levels of nerve growth factor (NGF), phosphorylation of Akt and Bad, dimerization of Bad and Bcl-xL, as well as the release of cytochrome c and the caspase-3 activity were measured. Moreover, these variables were also examined in vitro in HD-exposed VSC4.1 cells with or without a PI3K-specific agonist (IGF-1), and in HD-exposed VSC4.1 cells with or without a PI3K-specific inhibitor (LY294002) in the presence or absence of NGF. The data indicate that, as the concentration of HD increased, rats exhibited progressive gait abnormalities, and enhanced neuronal apoptosis in the rat sciatic nerve, compared with the results observed in the control group. Furthermore, HD significantly down-regulated NGF expression in the rat sciatic nerve. Moreover, suppression of NGF expression inhibited the phosphorylation of Akt and Bad. Meanwhile, an increase in the dimerization of Bad and Bcl-xL in mitochondria resulted in cytochrome c release and caspase-3 activation. In contrast, HD-induced apoptosis was eliminated by IGF-1. Additionally, NGF supplementation reversed the decrease in phosphorylation of Akt and Bad, as well as reversing the neuronal apoptosis in HD-exposed VSC4.1 cells. However, LY294002 blocked these effects of NGF. Collectively, our results demonstrate that mitochondrial-dependent apoptosis is induced by HD through NGF suppression via the PI3K/Akt pathway both in vivo and in vitro.

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Section: Introductionmentioning

confidence: 82%

2,5-Hexanedione mediates neuronal apoptosis through suppression of NGF via PI3K/Akt signaling in the rat sciatic nerve

et al. 2019

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“…Recent studies have shown that 2,5-HD promotes cell injury via regulating mitochondriadependent apoptosis (7,27). Oxidative stress leads to a state of imbalance between the levels of antioxidants that comprise the defense system and the production of free radicals (28).…”

Section: Resultsmentioning

confidence: 99%

Proapoptotic effects of 2,5‑hexanedione on pheochromocytoma cells via oxidative injury

Yuan

et al. 2019

Mol Med Report

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N-hexanes are prominent environmental pollutants that are able to cause neurotoxicity in vivo and in vitro. Central and peripheral neuropathies induced by n-hexane exposure are a major health concern. 2,5-Hexanedione (2,5-HD) is the most significant neurotoxic metabolite of n-hexane; however, little is known regarding the underlying mechanism of its neurotoxicity. Thus, the aim of the present study was to investigate the damaging effects of 2,5-HD on pheochromocytoma PC12 cells, and to explore the underlying mechanism. Cell viability was tested using a Cell Counting Kit-8 method, and the leakage of lactate dehydrogenase (LDH) from cells was measured using an LDH assay kit. Glutathione peroxidase (GSHPx) and superoxide dismutase (SOD) activities, and the level of malondialdehyde (MDA) were determined using corresponding assay kits. Apoptotic cells were detected using an annexin V-fluorescein isothiocyanate/propidium iodide (PI) apoptosis kit, and were subsequently observed by fluorescence microscopy. The relative expression levels of cleaved-caspase-3, Bcl-associated-X protein (Bax) and Bcl-2 were identified by western blotting. The results revealed that 2,5-HD was able to decrease the viability of PC12 cells and promoted the leakage of LDH in a concentrationdependent manner. Further analysis demonstrated that 2,5-HD decreased the activity of the antioxidative enzymes, SOD and GSHPx, and led to an increase in the levels of MDA in the supernatant of cultured PC12 cells. The annexin V/PI staining results revealed that the numbers of apoptotic cells were increased following treatment with 2,5-HD. In addition, 2,5-HD (5 and 10 mmol/l) led to significant increases in the expression levels of caspase-3 and Bax, with the concomitant downregulation of Bcl-2. The antioxidant N-acetylcysteine was identified to antagonize 2,5-HD-stimulated cleaved-caspase-3 and Bax upregulation, and Bcl-2 downregulation. Collectively, the results of the present study suggested that 2,5-HD exerts proapoptotic effects on PC12 cells via oxidative injury. These findings may be applied in the development of novel therapeutic strategies to treat neurological disorders associated with nhexane exposure.

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“…Recently, Qi and colleagues [68] exhaustively analysed the effects of 2,5-HD on mitochondria-related pathways in undifferentiated PC12 cells, showing that toxin-induced apoptosis occurs via mitochondria-induced activity of Caspase-3. Moreover, all these 2,5-HDinduced alterations were successfully prevented by treatment with the anti-oxidant taurine [69]. Unfortunately, the authors did not look at any components of the cytoskeleton in undifferentiated cells, so we cannot really compare the respective role of mitochondria-and MTbased effects in triggering cell death.…”

Section: Discussionmentioning

confidence: 99%

The imbalance between dynamic and stable microtubules underlies neurodegeneration induced by 2,5-hexanedione

Casagrande

Amadeo

Cartelli

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Exposure to environmental toxins, including hydrocarbon solvents, increases the risk of developing Parkinson's disease. An emergent hypothesis considers microtubule dysfunction as one of the crucial events in triggering neuronal degeneration in Parkinson's disease. Here, we used 2,5-hexanedione (2,5-HD), the toxic metabolite of n-hexane, to analyse the early effects of toxin-induced neurodegeneration on the cytoskeleton in multiple model systems. In PC12 cells differentiated with nerve growth factor for 5 days, we found that 2,5-HD treatment affected all the cytoskeletal components. Moreover, we observed alterations in microtubule distribution and stability, in addition to the imbalance of post-translational modifications of α-tubulin. Similar defects were also found in vivo in 2,5-HD-intoxicated mice. Interestingly, we also found that 2,5-HD exposure induced significant changes in microtubule stability in human skin fibroblasts obtained from Parkinson's disease patients harbouring mutations in PRKN gene, whereas it was ineffective in healthy donor fibroblasts, suggesting that the genetic background may really make the difference in microtubule susceptibility to this environmental Parkinson's disease-related toxin. In conclusion, by showing the imbalance between dynamic and stable microtubules in hydrocarbon-induced parkinsonism, our data support the crucial role of microtubule defects in triggering neurodegeneration.

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Taurine inhibits 2,5-hexanedione-induced oxidative stress and mitochondria-dependent apoptosis in PC12 cells

Cited by 26 publications

References 31 publications

2,5-Hexanedione mediates neuronal apoptosis through suppression of NGF via PI3K/Akt signaling in the rat sciatic nerve

2,5-Hexanedione mediates neuronal apoptosis through suppression of NGF via PI3K/Akt signaling in the rat sciatic nerve

Proapoptotic effects of 2,5‑hexanedione on pheochromocytoma cells via oxidative injury

The imbalance between dynamic and stable microtubules underlies neurodegeneration induced by 2,5-hexanedione

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