S-Allylmercapto-N-acetylcysteine (ASSNAC) protects cultured nerve cells from oxidative stress and attenuates experimental autoimmune encephalomyelitis

Savion, Naphtali; Izigov, Nira; Morein, Milana; Pri‐Chen, Sara; Kotev-Emeth, Shlomo

doi:10.1016/j.neulet.2014.09.034

Cited by 14 publications

(19 citation statements)

References 29 publications

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“…Increased oxidative stress may also play a role in MS progression (16). Therapies targeting oxidative stress by increasing reduced glutathione levels have demonstrated beneficial effects in experimental autoimmune encephalomyelitis (EAE) (19).…”

Section: Discussionmentioning

confidence: 99%

Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation

Bhargava¹,

Fitzgerald²,

Calabresi³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation

Bhargava¹,

Fitzgerald²,

Calabresi³

et al. 2017

JCI Insight

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“…Another option is S‐allylmercapto‐N‐acetylcysteine (ASSNAC) (Savion et al ., ). In the model of MS, mice with experimental autoimmune encephalomyelitis (EAE), spinal cord and brain GSH increased by 54 and 47%, respectively, following administration of ASSNAC (200 mg·kg −1 ·day −1 )and the clinical symptoms showed greater improvement than with NAC.…”

Section: Thiol‐based Redox Therapies In Neurodegenerative Diseasementioning

confidence: 97%

“…In the model of MS, mice with experimental autoimmune encephalomyelitis (EAE), spinal cord and brain GSH increased by 54 and 47%, respectively, following administration of ASSNAC (200 mg·kg −1 ·day −1 )and the clinical symptoms showed greater improvement than with NAC. ASSNAC activates Nrf2 and increases the expression of phase II detoxifying enzymes that include the x c − exchanger and GCL (Savion et al ., ).…”

Section: Thiol‐based Redox Therapies In Neurodegenerative Diseasementioning

confidence: 97%

“…On the other hand, Massie and colleagues observed that mice lacking the xCT subunit of the x c − exchanger were less susceptible to toxicity by 6(OH)DA, possibly because of reduced glutamate release (Massie et al ., ). Contrary to expectation, GSH levels in the SN were not reduced in xCT ‐/‐ mice (Gout et al ., ; De Groot and Sontheimer, ; Bridges et al ., ; Sontheimer and Bridges, ; Sunitha et al ., ; Savion et al ., ; Chen et al ., ).…”

Section: Thiol‐based Redox Therapies In Neurodegenerative Diseasementioning

confidence: 99%

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Redox‐based therapeutics in neurodegenerative disease

McBean

López

Wallner

2016

British J Pharmacology

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This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations 6(OH)DA, 6-hydroxydopamine; AD, Alzheimer's disease; ADME(T), absorption, distribution, metabolism and excretion/toxicity; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; ARE, antioxidant response element; ASSNAC, S-allylmercapto-N-acetyl cysteine; Aβ, amyloid-β; CA, carnosic acid; DMF, dimethylfumarate; EAE, experimental autoimmune encephalomyelitis; EpRE, electrophile response element; GCL, glutamate cysteine ligase; GR, glutathione reductase; Grx, glutaredoxin; GSK-3β, glycogen synthase kinase-3β; Keap1, Kelch-like ECH-associated protein-1; MMF, monomethylfumarate; MPTP, 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; MPO, myeloperoxidase; NAC, N-acetylcysteine; NACA, N-acetylcysteine amide; NOX, NADPH oxidase; NQO1, NAD(P)H quinone oxidoreductase-1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PD, Parkinson's disease; PS1, pre-senelin-1; RNS, reactive nitrogen species; SN, substantia nigra; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, functional subunit of the x c À exchanger Disruption of cerebral redox homeostasis is a common occurrence in a range of human neurodegenerative disorders, and although much is understood of mechanistic dysfunction, the gap between knowledge and the availability of effective therapies remains wide. In this review, we focus on the potential for developing therapeutic agents that promote the availability of thiol redox antioxidants or boost the antioxidant capacity of cells via stimulation of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, we discuss options for reducing ROS production by inhibition of NADPH oxidases (NOXs), limiting nitrative stress or targeting mitochondrial dysfunction. Other potential strategies for limiting oxidative stress in neurodegenerative disease include nutrient and vitamin supplementation and metal chelators, which are excluded from the discussion. These approaches are t...

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“…More than that, the highly hydrophobic nature of the s-allyl mercaptan moiety facilitates ASSNAC cellular penetration. Indeed, we demonstrated the ability of ASSNAC to increase expression of phase II detoxifying enzymes and glutathione level in cultured vascular endothelial cells, thus increasing the cellular protection against oxidative stress [ 15 ] and attenuating clinical symptoms of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis [ 16 ]. Our current study explores the ability of ASSNAC to increase glutathione content, GST gene expression and enzyme activity in C .…”

Section: Introductionmentioning

confidence: 99%

S-allylmercapto-N-acetylcysteine protects against oxidative stress and extends lifespan in Caenorhabditis elegans

et al. 2018

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S-allylmercapto-N-acetylcysteine (ASSNAC) was shown in our previous study to activate Nrf2-mediated processes and increase glutathione level and resistance to oxidative stress in cultured endothelial cells. In this study, we explored the antioxidant protective effect of ASSNAC in Caenorhabditis elegans (C. elegans). Treatment of gst-4 reporter strain (CL2166) with increasing concentrations of ASSNAC (0.2 to 20 mM) for 24 hours and with ASSNAC (10 mM) for various time periods demonstrated a significant concentration- and time-dependent increase in Glutathione S-transferase (GST) gene expression (up to 60-fold at 20 mM after 24 hours). In addition, ASSNAC (2 mM; 24 hours) treatment of C. elegans strains N2 (wild type strain), gst-4 reporter (CL2166) and temperature sensitive sterile strain (CF512) significantly increased GST enzyme activity by 1.9-, 1.5- and 1.8-fold, respectively. ASSNAC (2.0 mM; 24 hours) increased the reduced glutathione content in N2 and CF512 strains by 5.9- and 4.9-fold, respectively. Exposure of C. elegans (N2 strain) to a lethal concentration of H2O2 (3.5 mM; 120 min) resulted in death of 88% of the nematodes while pretreatment with ASSNAC (24 hours) reduced nematodes death in a concentration-dependent manner down to 8% at 2.0 mM. C. elegans nematodes (strain CF512) cultured on agar plates containing ASSNAC (0.5 to 5.0 mM) demonstrated a significant increase in lifespan compared to control (mean lifespan 26.45 ± 0.64 versus 22.90 ± 0.59 days; log-rank p ≤ 0.001 at 2.0 mM) with a maximal lifespan of 40 versus 36 days. In conclusion, ASSNAC up-regulates the GST gene expression and enzyme activity as well as the glutathione content in C. elegans nematodes and thereby increases their resistance to oxidative stress and extends their lifespan.

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S-Allylmercapto-N-acetylcysteine (ASSNAC) protects cultured nerve cells from oxidative stress and attenuates experimental autoimmune encephalomyelitis

Cited by 14 publications

References 29 publications

Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation

Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation

Redox‐based therapeutics in neurodegenerative disease

S-allylmercapto-N-acetylcysteine protects against oxidative stress and extends lifespan in Caenorhabditis elegans

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