The neuroprotective effect of N-acetylcysteine in spinal cord-injured rats

Olakowska, Edyta; Marcol, Wiesław; Właszczuk, Adam; Woszczycka-Korczyńska, Izabella; Lewin–Kowalik, Joanna

doi:10.17219/acem/65478

Cited by 8 publications

(8 citation statements)

References 25 publications

(26 reference statements)

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“…Furthermore, NAC has been reported to possess antioxidant properties by scavenging reactive oxygen species (ROS) and also inhibit the activity of cyclooxygenase-2 and membrane lipid peroxidation induced by inflammation [18,19]. Coombes et al suggest that NAC has reno-protective activities in chronic kidney disease [20] and neuro-protective effect on spinal cord-injury [21]. Preliminary data in rat model revealed that oral treatment with high-dose NAC during early silica exposure can ameliorate the activity of proinflammatory cytokines, down-regulating ROS, and mitochondrial apoptosis signaling, thus attenuating subsequent lung fibrosis, suggesting the potential of NAC in the treatment for silica-induced lung fibrosis [22,23].…”

Section: Introductionmentioning

confidence: 99%

N-acetylcysteine tiherapeutically protects against pulmonary fibrosis in a mouse model of silicosis

et al. 2019

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Silicosis is a lethal pneumoconiosis disease characterized by chronic lung inflammation and fibrosis. The present study was to explore the effect of against crystalline silica (CS)-induced pulmonary fibrosis. A total of 138 wild-type C57BL/6J mice were divided into control and experimental groups, and killed on month 0, 1, 2, 3, 4, and 5. Different doses of N-acetylcysteine (NAC) were gavaged to the mice after CS instillation to observe the effect of NAC on CS induced pulmonary fibrosis and inflammation. The pulmonary injury was evaluated with Hematoxylin and eosin/Masson staining. Reactive oxygen species level was analyzed by DCFH-DA labeling. Commercial ELISA kits were used to determine antioxidant activity (T-AOC, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) and cytokines (TNF-α, IL-1β, IL-4, and IL-6). The expression of oxidising enzymes (NOX2, iNOS, SOD2, and XO) were detected by real time PCR. Immunohistochemistry (IHC) staining was performed to examine epithelial-mesenchymal transition-related markers. The mice treated with NAC presented markedly reduced CS-induced pulmonary injury and ameliorated CS-induced pulmonary fibrosis and inflammation. The level of malondialdehyde was reduced, while the activities of GSH-PX, SOD, and T-AOC were markedly enhanced by NAC. We also found the down-regulation of oxidising enzymes (NOX2, iNOS, SOD2, and XO) after NAC treatment. Moreover, E-cadherin expression was increased while vimentin and Cytochrome C expressions were decreased by NAC. These encouraging findings suggest that NAC exerts pulmonary protective effects in CS-induced pulmonary fibrosis and might be considered as a promising agent for the treatment of silicosis.

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Section: Introductionmentioning

confidence: 99%

N-acetylcysteine tiherapeutically protects against pulmonary fibrosis in a mouse model of silicosis

et al. 2019

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“…Previous studies in rats using NAC or NACA to manage SCI have found beneficial therapeutic effects. 8 , 9 , 27 , 28 , 48 , 49 In this study, NACA was first given to naïve mice to reproduce a previously published dosing strategy that increases cellular GSH to demonstrate its potential for augmenting GSH within the spinal cord. After demonstrating the efficacy of our approach in naïve mice, both 4- and 14-MO mice received SCI and were treated with NACA, which did augment spinal GSH and improved the GSH/GSSG redox ratio.…”

Section: Discussionmentioning

confidence: 99%

Advanced Age and Neurotrauma Diminish Glutathione and Impair Antioxidant Defense after Spinal Cord Injury

Stewart

Glaser

Mott

et al. 2022

Journal of Neurotrauma

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Advanced age at the time of spinal cord injury (SCI) exacerbates damage from reactive oxygen species (ROS). Mechanisms underlying this age-dependent response are not well understood and may arise from decreased antioxidant defense. We investigated how spinal cord levels of the antioxidant glutathione (GSH), and its regulation, change with age and SCI. GSH is used by GSH peroxidase to sequester ROS and is recycled by GSH reductase. Male and female, 4- and 14-month-old (MO) mice received a 60 kDyn contusion SCI, and the levels of GSH and its regulatory enzymes were evaluated at one and three days post-injury (dpi). The mice with SCI were treated with N-acetylcysteine-amide (NACA; 150 mg/kg), a cysteine supplement that increases GSH, to determine effects on functional and histological outcomes. GSH was decreased with older age in sham mice, and an SCI-dependent depletion was observed in 4-MO mice by three dpi. Neither age nor injury affected the abundance of proteins regulating GSH synthesis or recycling. GSH peroxidase activity, however, increased after SCI only in 4-MO mice. In contrast, GSH peroxidase activity was increased in 14-MO sham mice, indicating that spinal cords of older mice have an elevated oxidative state. Indeed, 14-MO sham mice had more oxidized protein (3-nitrotyrosine [3-NT]) within their spinal cords compared with 4-MO sham mice. Only 4-MO mice had significant injury-induced increases in 3-NT at three dpi. NACA treatment restored GSH and improved the redox environment in injured 4- and 14-MO mice at one dpi; however, three days of NACA delivery did not improve motor, sensory, or anatomical deficits at 28 dpi in 4-MO mice and trended toward toxicity in all outcomes in 14-MO mice. Our observation suggests that GSH levels at acute stages of SCI play a minimal role in age-dependent outcomes reported after SCI in mice. Collective results implicate elements of injury occurring after three dpi, such as inflammation, as key regulators of age-dependent effects.

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“…Targeting GSH dysfunction after SCI has been performed by providing cysteine analogs such as n-acetylcysteine (NAC) or a more recently developed n -acetylcysteine amide (NACA) which has better bioavailability within the spinal cord ( Kamencic et al, 2001 ; Hanci et al, 2010 ; Karalija et al, 2012 , 2014 ; Patel et al, 2014 ; Guo et al, 2015 ; Olakowska et al, 2017 ; Stewart et al, 2022b ). Treating SCI in rats with NAC or NACA restores cellular levels of GSH, protects against oxidative stress, and improves mitochondrial, behavioral, and histopathological outcomes ( Kamencic et al, 2001 ; Hanci et al, 2010 ; Karalija et al, 2012 , 2014 ; Patel et al, 2014 ; Guo et al, 2015 ; Olakowska et al, 2017 ).…”

Section: Aging In Animal Modelsmentioning

confidence: 99%

Section: Aging In Animal Modelsmentioning

confidence: 99%

Improving translatability of spinal cord injury research by including age as a demographic variable

Stewart

Jones

Gensel

2022

Front. Cell. Neurosci.

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Pre-clinical and clinical spinal cord injury (SCI) studies differ in study design, particularly in the demographic characteristics of the chosen population. In clinical study design, criteria such as such as motor scores, neurological level, and severity of injury are often key determinants for participant inclusion. Further, demographic variables in clinical trials often include individuals from a wide age range and typically include both sexes, albeit historically most cases of SCI occur in males. In contrast, pre-clinical SCI models predominately utilize young adult rodents and typically use only females. While it is often not feasible to power SCI clinical trials to test multi-variable designs such as contrasting different ages, recent pre-clinical findings in SCI animal models have emphasized the importance of considering age as a biological variable prior to human experiments. Emerging pre-clinical data have identified case examples of treatments that diverge in efficacy across different demographic variables and have elucidated several age-dependent effects in SCI. The extent to which these differing or diverging treatment responses manifest clinically can not only complicate statistical findings and trial interpretations but also may be predictive of worse outcomes in select clinical populations. This review highlights recent literature including age as a biological variable in pre-clinical studies and articulates the results with respect to implications for clinical trials. Based on emerging unpredictable treatment outcomes in older rodents, we argue for the importance of including age as a biological variable in pre-clinical animal models prior to clinical testing. We believe that careful analyses of how age interacts with SCI treatments and pathophysiology will help guide clinical trial design and may improve both the safety and outcomes of such important efforts.

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The neuroprotective effect of N-acetylcysteine in spinal cord-injured rats

Cited by 8 publications

References 25 publications

N-acetylcysteine tiherapeutically protects against pulmonary fibrosis in a mouse model of silicosis

N-acetylcysteine tiherapeutically protects against pulmonary fibrosis in a mouse model of silicosis

Advanced Age and Neurotrauma Diminish Glutathione and Impair Antioxidant Defense after Spinal Cord Injury

Improving translatability of spinal cord injury research by including age as a demographic variable

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