Effect of alpha-ketoglutarate and<i>N</i>-acetyl cysteine on cyanide-induced oxidative stress mediated cell death in PC12 cells

Satpute, Ravindra M; Hariharakrishnan, J.; Bhattacharya, Rahul

doi:10.1177/0748233710365695

Cited by 23 publications

(18 citation statements)

References 52 publications

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“…The link between cystinosin loss-of-function and increased oxidative stress have been long-established 10,11,22,23 . αKG is a well-known antioxidant and its level can be increased by cells in response to oxidative stress contributing to the prevention and/or treatment of several disorders induced by oxidative stress [19][20][21] . This is done through downregulation of the mitochondrial enzyme AKGDH, reported to be severely diminished in human pathologies where oxidative stress is thought to play a vital role 21 .…”

Section: Discussionmentioning

confidence: 99%

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

Jamalpoor

Gelder

Yengej

et al. 2020

Preprint

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Nephropathic cystinosis is a severe monogenetic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established proximal tubulopathy. Here, we developed a new therapeutic strategy by applying an omics-based strategy to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a key metabolite linking cystinosin loss, lysosomal autophagy defect and proximal tubular impairment in cystinosis. This insight offered a bicalutamide-cysteamine combination treatment as a novel dual target pharmacological approach for the phenotypical correction of cystinotic proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.

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Section: Discussionmentioning

confidence: 99%

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

Jamalpoor

Gelder

Yengej

et al. 2020

Preprint

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“…For example, α -KG is known to protect against oxidative stress (Zdzisińska et al 2017 ). In fact, α -KG has been shown to protect against cyanide poisoning both in vitro and in vivo ( Satpute et al 2010 ; Bhattacharya et al 2002 ). Like OPs, cyanide is also a neurotoxin which causes oxidative stress by the inhibition of numerous antioxidant enzymes (Müller and Krieglstein 1995 ; Ardelt et al 1994 ; Solomonson 1983 ).…”

Section: Discussionmentioning

confidence: 99%

Discovery of treatment for nerve agents targeting a new metabolic pathway

et al. 2020

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The inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX. Proteomic and metabolomic profiling resulted in the identification of several enzymes and metabolic precursors involved in glycolysis and the TCA cycle. All lines of experimental evidence indicated that there was a blockade of the TCA cycle at isocitrate dehydrogenase 2, which converts isocitrate to α-ketoglutarate. Using a primary beating cardiomyocyte cell model, we were able to determine that the supplementation of α-ketoglutarate subsequently rescued cells from the acute effects of VX poisoning. This study highlights the broad impacts that VX has and how understanding these mechanisms could result in new therapeutics such as α-ketoglutarate.

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“…Cyanide has long been known to stimulate ROS/RNS that contribute to its neurological and cardiovascular toxicity[49–52]. Additional in-vitro and in-vivo studies have also revealed that GSH depletion and elevated lipid peroxidation may contribute to the toxic effects of cyanide poisoning[50,53]. …”

Section: 0 Overview Of the Evidence For Oxidative Stress In Cwas Anmentioning

confidence: 99%

“…In models of chloropicrin-induced epithelial cell toxicity, NAC has been shown to prevent cell vacuolization and preserve cell viability[33]. For blood agents, NAC has been shown in cell culture models to protect cells exposed to cyanide from GSH depletion and lipid peroxidation[53]. It has also been used in several studies which have reported positive outcomes associated with NAC administration after arsenic poisoning[82].…”

Section: 0 Potential Antioxidant Therapies: Mechanisms Efficacy Amentioning

confidence: 99%

Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals

McElroy

Day

2016

Biochemical Pharmacology

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The continuing horrors of military conflicts and terrorism often involve the use of chemical warfare agents (CWAs) and toxic industrial chemicals (TICs). Many CWA and TIC exposures are difficult to treat due to the danger they pose to first responders and their rapid onset that can produce death shortly after exposure. While the specific mechanism(s) of toxicity of these agents are diverse, many are associated either directly or indirectly with increased oxidative stress in affected tissues. This has led to the exploration of various antioxidants as potential medical countermeasures for CWA/TIC exposures. Studies have been performed across a wide array of agents, model organisms, exposure systems, and antioxidants, looking at an almost equally diverse set of endpoints. Attempts at treating CWAs/TICs with antioxidants have met with mixed results, ranging from no effect to nearly complete protection. The aim of this commentary is to summarize the literature in each category for evidence of oxidative stress and antioxidant efficacy against CWAs and TICs. While there is great disparity in the data concerning methods, models, and remedies, the outlook on antioxidants as medical countermeasures for CWA/TIC management appears promising.

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Effect of alpha-ketoglutarate andN-acetyl cysteine on cyanide-induced oxidative stress mediated cell death in PC12 cells

Cited by 23 publications

References 52 publications

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

Discovery of treatment for nerve agents targeting a new metabolic pathway

Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals

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