N-Acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress

Unnithan, Ajay S.; Jiang, Yihui; Rumble, Jennifer L.; Pulugulla, Sree H.; Posimo, Jessica M.; Gleixner, Amanda M.; Leak, Rehana K.

doi:10.1016/j.neulet.2013.12.023

Cited by 24 publications

(19 citation statements)

References 43 publications

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“…We have established that signal in this assay is reduced by application of the glutathione synthesis inhibitor buthionine sulfoximine and increased by the glutathione precursor N-acetyl cysteine [58, 63, 67, 68]. Reduced glutathione levels were specifically measured by the GSH-Glo glutathione assay according to the manufacturer’s instructions (Cat.…”

Section: Methodsmentioning

confidence: 99%

Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury

et al. 2015

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Astrocytes are one of the major cell types to combat cellular stress and protect neighboring neurons from injury. In order to fulfill this important role, astrocytes must sense and respond to toxic stimuli, perhaps including stimuli that are severely stressful and kill some of the astrocytes. The present study demonstrates that primary astrocytes that managed to survive severe proteotoxic stress were protected against subsequent challenges. These findings suggest that the phenomenon of preconditioning or tolerance can be extended from mild to severe stress for this cell type. Astrocytic stress adaptation lasted at least 96 hours, the longest interval tested. Heat shock protein 70 (Hsp70) was raised in stressed astrocytes, but inhibition of neither Hsp70 nor Hsp32 activity abolished their resistance against a second proteotoxic challenge. Only inhibition of glutathione synthesis abolished astrocytic stress adaptation, consistent with our previous report. Primary neurons were plated upon previously stressed astrocytes and the co-cultures were then exposed to another proteotoxic challenge. Severely stressed astrocytes were still able to protect neighboring neurons against this injury and the protection was unexpectedly independent of glutathione synthesis. Stressed astrocytes were even able to protect neurons after simultaneous application of proteasome and Hsp70 inhibitors, which otherwise elicited synergistic, severe loss of neurons when applied together. Astrocyte-induced neuroprotection against proteotoxicity was not elicited with astrocyte-conditioned media, suggesting that physical cell-to-cell contacts may be essential. These findings suggest that astrocytes may adapt to severe stress so that they can continue to protect neighboring cell types from profound injury.

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Section: Methodsmentioning

confidence: 99%

Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury

et al. 2015

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“…However, this phenomenon of 'survival of the fittest astrocytes' cannot be generalized to all cell types. In some systems, the cells that survive severe stress are not resistant, but are actually sensitized to subsequent stress, so that the two hits of severe stress are synergistic in their toxic effects in these populations (Boger et al 2010;Carvey et al 2006;Gao and Hong 2011;Manning-Bog and Langston 2007;Sulzer 2007;Unnithan et al 2012Unnithan et al , 2013Weidong et al 2009;Zhu et al 2001Zhu et al , 2007. In short, one might expect the direction of the stress response, i.e., whether it will elicit pro-survival or pro-death responses, to depend on cell type, heat shock protein expression, antioxidant defenses, dose and duration of the injury, previous exposures to other stressors, brain region, animal age, nutrient intake, physical activity levels, disease stage, and numerous other endogenous and environmental variables (Leak 2014).…”

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confidence: 99%

Heat shock proteins in neurodegenerative disorders and aging

Leak

2014

J. Cell Commun. Signal.

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Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stressinduced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

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“…Our recent in vitro studies demonstrate that NAC can robustly protect cortical neurons and neuroblastoma cells against proteasome inhibitors and oxidative stress (Jiang et al, 2013; Posimo et al, 2013; Unnithan et al, 2012; Unnithan et al, 2014). Indeed, NAC was so protective that it prevented cell death in response to severe, dual hits of the proteasome inhibitor MG132 and hydrogen peroxide (Unnithan et al, 2012; Unnithan et al, 2014). We also discovered that NAC can prevent loss of heat shock protein defenses in neuroblastoma cells treated with high concentrations of MG132 and that inhibitors of heat shock protein 70 (Hsp70) abolished NAC-mediated protection (Jiang et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…For example, we recently showed that NAC prevents neurodegeneration in multiple cellular models of neurodegenerative disorders (Jiang et al, 2013; Posimo et al, 2013; Unnithan et al, 2012; Unnithan et al, 2014). Consistent with these observations, Clark and colleagues have shown that NAC can prevent dopaminergic terminal loss and α-synucleinopathy in a transgenic mouse model of Parkinson's disease (Clark et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Investigation of the therapeutic potential of N-acetyl cysteine and the tools used to define nigrostriatal degeneration in vivo

Nouraei

Zarger

Weilnau

et al. 2016

Toxicology and Applied Pharmacology

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The glutathione precursor N-acetyl-L-cysteine (NAC) is currently being tested on Parkinson's patients for its neuroprotective properties. Our studies have shown that NAC can elicit protection in glutathione-independent manners in vitro. Thus, the goal of the present study was to establish an animal model of NAC-mediated protection in which to dissect the underlying mechanism. Mice were infused intrastriatally with the oxidative neurotoxicant 6-hydroxydopamine (6-OHDA; 4 μg) and administered NAC intraperitoneally (100 mg/kg). NAC-treated animals exhibited higher levels of the dopaminergic terminal marker tyrosine hydroxylase (TH) in the striatum 10d after 6-OHDA. As TH expression is subject to stress-induced modulation, we infused the tracer FluoroGold into the striatum to retrogradely label nigrostriatal projection neurons. As expected, nigral FluoroGold staining and cell counts of FluoroGold+ profiles were both more sensitive measures of nigrostriatal degeneration than measurements relying on TH alone. However, NAC failed to protect dopaminergic neurons 3 weeks following 6-OHDA, an effect verified by four measures: striatal TH levels, nigral TH levels, nigral TH+ cell counts, and nigral FluoroGold levels. Some degree of mild toxicity of FluoroGold and NAC was evident, suggesting that caution must be exercised when relying on FluoroGold as a neuron-counting tool and when designing experiments with long-term delivery of NAC—such as clinical trials on patients with chronic disorders. Finally, the strengths and limitations of the tools used to define nigrostriatal degeneration are discussed.

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N-Acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress

Cited by 24 publications

References 43 publications

Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury

Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury

Heat shock proteins in neurodegenerative disorders and aging

Investigation of the therapeutic potential of N-acetyl cysteine and the tools used to define nigrostriatal degeneration in vivo

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