Hydrogen sulfide antagonizes homocysteine-induced neurotoxicity in PC12 cells

Tang, Xiao‐Qing; Shen, Xintian; Huang, Yi-E; Ren, Yi; Chen, Rong-Qian; Hu, Bi Ying; He, Jianqin; Yin, Wei-Lan; Xu, Jie; Jiang, Zhi‐Sheng

doi:10.1016/j.neures.2010.07.2039

Cited by 51 publications

(31 citation statements)

References 42 publications

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“…H 2 S, as a reducing agent and an antioxidant molecule, has been previously shown to protect various cell types from oxidative injury (33)(34)(35)(36). Based on the current results, we hypothesize that H 2 S provides a reducing/antioxidant intracellular environment that contributes to the maintenance of normal mitochondrial function.…”

Section: Discussionsupporting

confidence: 66%

Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function

Suzuki¹,

Oláh²,

Módis³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

259

256

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The goal of the present studies was to investigate the role of changes in hydrogen sulfide (H 2 S) homeostasis in the pathogenesis of hyperglycemic endothelial dysfunction. Exposure of bEnd3 microvascular endothelial cells to elevated extracellular glucose (in vitro "hyperglycemia") induced the mitochondrial formation of reactive oxygen species (ROS), which resulted in an increased consumption of endogenous and exogenous H 2 S. Replacement of H 2 S or overexpression of the H 2 S-producing enzyme cystathionine-γ-lyase (CSE) attenuated the hyperglycemia-induced enhancement of ROS formation, attenuated nuclear DNA injury, reduced the activation of the nuclear enzyme poly(ADP-ribose) polymerase, and improved cellular viability. In vitro hyperglycemia resulted in a switch from oxidative phosphorylation to glycolysis, an effect that was partially corrected by H 2 S supplementation. Exposure of isolated vascular rings to high glucose in vitro induced an impairment of endothelium-dependent relaxations, which was prevented by CSE overexpression or H 2 S supplementation. siRNA silencing of CSE exacerbated ROS production in hyperglycemic endothelial cells. Vascular rings from CSE −/− mice exhibited an accelerated impairment of endothelium-dependent relaxations in response to in vitro hyperglycemia, compared with wild-type controls. Streptozotocininduced diabetes in rats resulted in a decrease in the circulating level of H 2 S; replacement of H 2 S protected from the development of endothelial dysfunction ex vivo. In conclusion, endogenously produced H 2 S protects against the development of hyperglycemia-induced endothelial dysfunction. We hypothesize that, in hyperglycemic endothelial cells, mitochondrial ROS production and increased H 2 S catabolism form a positive feed-forward cycle. H 2 S replacement protects against these alterations, resulting in reduced ROS formation, improved endothelial metabolic state, and maintenance of normal endothelial function.

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Section: Discussionsupporting

confidence: 66%

Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function

Suzuki¹,

Oláh²,

Módis³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

259

256

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show abstract

“…Furthermore, both elevation of Hcy and decrease of H 2 S are detected in the brains of AD patients [49] . Therefore, we have previously explored if H 2 S directly antagonizes the toxicity of Hcy to neuronal cells, and our previous data revealed that H 2 S could attenuate the neurotoxicity of Hcy [31] . It has been reported that H 2 S serves as a protective gaseous signaling molecule in the nervous system by preserving mitochondrial function [50,51] .…”

Section: Discussionmentioning

confidence: 99%

“…Hydrogen sulfide (H 2 S), the third gaseous mediator, has recently been recognized as an important endogenous neuromodulator and neuroprotectant [26][27][28][29] . The most recent in vitro studies by our group have demonstrated that Hcy-associated neurotoxicity to PC12 cells is due to reduced endogenous generation of H 2 S [30] and that supplementation of sodium hydrosulfide (NaHS), the H 2 S-donor, ameliorates the Hcy elicited-neurotoxicity in PC12 cells [31] . However, the mechanisms underlying the protective effect of H 2 S against Hcy neurotoxicity are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway

Wei

et al. 2014

Acta Pharmacol Sin

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Aim: Homocysteine (Hcy) can elicit neuronal cell death, and hyperhomocysteinemia is a strong independent risk factor for Alzheimer's disease. The aim of this study was to examine the effects of hydrogen sulfide (H 2 S) on Hcy-induced endoplasmic reticulum (ER) stress and neuronal apoptosis in rat hippocampus. Methods: Adult male SD rats were intracerebroventricularly (icv) injected with Hcy (0.6 μmol/d) for 7 d. Before Hcy injection, the rats were treated with NaHS (30 or 100 μmol·kg -1 ·d -1 , ip) and/or k252a (1 μg/d, icv) for 2 d. The apoptotic neurons were detected in hippocampal coronal slices with TUNEL staining. The expression of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cleaved caspase-12, and BDNF in the hippocampus were examined using Western blotting assays. The generation of H 2 S in the hippocampus was measured with the NNDPD method. Results: Hcy markedly inhibited the production of endogenous H 2 S and increased apoptotic neurons in the hippocampus. Furthermore, Hcy induced ER stress responses in the hippocampus, as indicated by the upregulation of GRP78, CHOP, and cleaved caspase-12. Treatment with the H 2 S donor NaHS increased the endogenous H 2 S production and BDNF expression in a dosedependent manner, and significantly reduced Hcy-induced neuronal apoptosis and ER stress responses in the hippocampus. Treatment with k252a, a specific inhibitor of TrkB (the receptor of BDNF), abolished the protective effects of NaHS against Hcy-induced ER stress in the hippocampus. Conclusion: H 2 S attenuates ER stress and neuronal apoptosis in the hippocampus of Hcy-treated rats via upregulating the BDNF-TrkB pathway.

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“…Endogenous levels of H 2 S of between 50 and 160 M are detected in the brains of humans (40). In the brains of AD patients, lower levels of H 2 S as well as accumulation of homocysteine (Hcy), a strong risk factor for the development of Alzheimer's disease (AD), are observed (71,72). Neurotoxicity of elevated Hcy is associated with inhibition of endogenous H 2 S generation and downregulation of expression and activity of CBS in PC12 cells, which is mediated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation.…”

Section: H 2 S: a Novel Therapeutic Agent In Age-associated Diseases?mentioning

confidence: 99%

Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases

Zhang

Tang

Zhong

et al. 2013

Molecular and Cellular Biology

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156

109

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Hydrogen sulfide (H 2 S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide. It is physiologically generated by cystathionine-␥-lyase, cystathionine-␤-synthase, and 3-mercaptopyruvate sulfurtransferase. H 2 S has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems. Substantial evidence shows that H 2 S is involved in aging by inhibiting free-radical reactions, activating SIRT1, and probably interacting with the age-related gene Klotho. Moreover, H 2 S has been shown to have therapeutic potential in age-associated diseases. This article provides an overview of the physiological functions and effects of H 2 S in aging and age-associated diseases, and proposes the potential health and therapeutic benefits of H 2 S.

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Hydrogen sulfide antagonizes homocysteine-induced neurotoxicity in PC12 cells

Cited by 51 publications

References 42 publications

Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function

Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function

Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway

Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases

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