Effects Of N-acetylcysteine Treatment Research Articles

N-Acetylcysteine normalizes brain oxidative stress and neuroinflammation observed after protracted ethanol abstinence: a preclinical study in long-term ethanol-experienced male rats

RationaleUsing a preclinical model based on the Alcohol Deprivation Effect (ADE), we have reported that N-Acetylcysteine (NAC) can prevent the relapse-like drinking behaviour in long-term ethanol-experienced male rats.ObjectivesTo investigate if chronic ethanol intake and protracted abstinence affect several glutamate transporters and whether NAC, administered during the withdrawal period, could restore the ethanol-induced brain potential dysfunctions. Furthermore, the antioxidant and anti-inflammatory effects of NAC during abstinence in rats under the ADE paradigm were also explored.MethodsThe expression of GLT1, GLAST and xCT in nucleus accumbens (Nacc) and dorsal striatum (DS) of male Wistar was analysed after water and chronic ethanol intake. We used the model based on the ADE within another cohort of male Wistar rats. During the fourth abstinence period, rats were treated for 9 days with vehicle or NAC (60, 100 mg/kg; s.c.). The effects of NAC treatment on (i) glutamate transporters expression in the Nacc and DS, (ii) the oxidative status in the hippocampus (Hip) and amygdala (AMG) and (iii) some neuroinflammatory markers in prefrontal cortex (PFC) were tested.ResultsNAC chronic administration during protracted abstinence restored oxidative stress markers (GSSG and GGSH/GSH) in the Hip. Furthermore, NAC was able to normalize some neuroinflammation markers in PFC without normalizing the observed downregulation of GLT1 and GLAST in Nacc.ConclusionsNAC restores brain oxidative stress and neuroinflammation that we previously observed after protracted ethanol abstinence in long-term ethanol-experienced male rats. This NAC effect could be a plausible mechanism for its anti-relapse effect. Also, brain oxidative stress and neuroinflammation could represent and identify plausible targets for searching new anti-relapse pharmacotherapies.

Effect of N-acetyl-cysteine treatment on sensorineural hearing loss: a meta-analysis.

N‐acetyl‐cysteine (NAC) is an efficacious treatment for sensorineural hearing loss in animal models, such as noise‐induced hearing loss (NIHL), however previous research into the effect of NAC on patients with hearing loss produced contradictory results. In this study, we investigated the effect of NAC treatment on sensorineural hearing loss. PubMed, Web of Science and Embase databases were searched in their entirety using the key words: hearing loss, NAC, N‐acetylcysteine, and sensorineural hearing loss. Studies which included assessment of hearing loss with pure‐tone threshold (PTA) data were selected. Eligible studies regarding the effects of NAC treatment on patients with hearing loss were collected by two independent reviewers. A total of 1197 individuals were included from seven published studies. Two studies reported data for a sudden idiopathic sensorineural hearing loss (SISNHL) group. Three studies reported data for a NIHL group. Other studies reported data for drug‐induced hearing loss. The meta‐analysis demonstrated that the overall effect of NAC treatment on sensorineural hearing loss was invalid. However, NAC treatment was linked with improved patient outcomes of hearing tests in cases of sudden hearing loss, but did not prevent hearing loss induced by noise or ototoxicity. However, there is a need for better‐designed studies with larger samples to further prove the correlation between the effect of NAC and hearing loss.

Effects of Antioxidant on Oxidative Stress and Autophagy in Bronchial Epithelial Cells Exposed to Particulate Matter and Cigarette Smoke Extract.

BackgroundWe evaluated the effect of particulate matter (PM) and cigarette smoke extract (CSE) on bronchial epithelial cell survival, as well as oxidative stress and autophagy levels. Moreover, we aimed to assess the effect of the antioxidant N-acetylcysteine (NAC) on the adverse effects of PM and CSE exposure.MethodsNormal human bronchial epithelial cells (BEAS-2B cells) were exposed to urban PM with or without CSE, after which cytotoxic effects, including oxidative stress and autophagy levels, were measured. After identifying the toxic effects of urban PM and CSE exposure, the effects of NAC treatment on cell damage were evaluated.ResultsUrban PM significantly decreased cell viability in a concentration-dependent manner, which was further aggravated by simultaneous treatment with CSE. Notably, pretreatment with NAC at 10 mM for 1 hour reversed the cytotoxic effects of PM and CSE co-exposure. Treatment with 1, 5, and 10 mM NAC was shown to decrease reactive oxygen species levels induced by exposure to both PM and CSE. Additionally, the autophagy response assessed via LC3B expression was increased by PM and CSE exposure, and this also attenuated by NAC treatment.ConclusionThe toxic effects of PM and CSE co-exposure on human bronchial epithelial cells, including decreased cell viability and increased oxidative stress and autophagy levels, could be partly prevented by NAC treatment.

Effects of N-acetylcysteine treatment on ethanol’s rewarding properties and dopaminergic alterations in mesocorticolimbic and nigrostriatal pathways

Recent reports have shown that N-acetylcysteine (N-AC) has beneficial effects in the treatment of cocaine and nicotine abuse. Considering the similar neurobiologic mechanisms involved in the development of addiction to different drugs, N-AC treatment could be useful in the treatment of ethanol abuse. The rewarding properties of the drugs of abuse plays an important role in the development of addiction and can be studied using the conditioned place preference (CPP) paradigm. Thus, to study the effects of N-AC treatment in the rewarding effects of ethanol, we investigated the effects of N-AC administration in the ethanol-induced CPP and neurochemical alterations within the mesocorticolimbic and the nigrostriatal dopaminergic pathways. Adult male Swiss mice were pretreated with N-AC (60 or 120 mg/kg intraperitoneal) and tested for the development, expression, or extinction of the ethanol-induced CPP. Another cohort of animals received N-AC (60 or 120 mg/kg intraperitoneal) 2-h before an acute administration of ethanol and had their brains removed for dopamine and its metabolites quantification in the mesocorticolimbic and nigrostriatal pathways. Pretreatment with N-AC (120 mg/kg) blocked the development of ethanol-induced CPP. On the other hand, N-AC at both doses did not alter the expression nor the extinction of ethanol-induced CPP. N-AC increased 3,4-dihydroxyphenylacetic acid content in the medial prefrontal cortex and dopaminergic turnover within the substantia nigra. Besides that, there was an increase in dopamine content in the nucleus accumbens of ethanol-treated animals. In summary, N-AC treatment blocked the development of ethanol CPP, without altering ethanol effects on dopaminergic neurotransmission.

N-acetyl cysteine treatment preserves mitochondrial indices of functionality in the brain of hyperammonemic mice.

Aim of the studyAcute or chronic live failure could result in hyperammonemia and hepatic encephalopathy (HE). HE is a clinical complication characterized by severe cognitive dysfunction and coma. The ammonium ion (NH4+) is the most suspected toxic molecule involved in the pathogenesis of HE. NH4+ is a neurotoxic agent. Different mechanisms, including oxidative/nitrosative stress, inflammatory response, excitotoxicity, and mitochondrial impairment, are proposed for NH4+-induced neurotoxicity. N-acetyl cysteine (NAC) is a well-known thiol-reductant and antioxidant agent. Several investigations also mentioned the positive effects of NAC on mitochondrial function. In the current study, the effect of NAC treatment on brain mitochondrial indices and energy status was investigated in an animal model of HE.Material and methodsAcetaminophen (APAP)-induced acute liver failure was induced by a single dose of the drug (800 mg/kg, i.p.) to C57BL/6J mice. Plasma and brain levels of NH4+ were measured. Then, brain mitochondria were isolated, and several indices, including mitochondrial depolarization, ATP level, lipid peroxidation, glutathione content, mitochondrial permeabilization, and dehydrogenase activity, were assessed.ResultsA significant increase in plasma and brain NH4+ was evident in APAP-treated animals. Moreover, mitochondrial indices of functionality were impaired, and mitochondrial oxidative stress biomarkers were significantly increased in APAP-treated mice. It was found that NAC treatment (100, 200, and 400 mg/kg, i.p.) significantly mitigated mitochondrial impairment in the brain of APAP-treated animals.ConclusionsThese data suggest the effects of NAC on brain mitochondrial function and energy status as a pivotal mechanism involved in its neuroprotective properties during HE.

Brain Oxidative Stress and Neurodegeneration in the Ketamine Model of Schizophrenia during Antipsychotic Treatment: Effects of N-Acetylcysteine Treatment

We aimed to investigate the effect of N-acetylcysteine (NAC) on brain oxidative stress and on the response to therapy with clozapine or haloperidol in the ketamine model of schizophrenia. Mice received intraperitoneal (i.p.) injections of either saline, ketamine (30 mg/kg), NAC (50 mg/kg), ketamine + NAC, ketamine + clozapine (1.5 mg/kg), ketamine + clozapine + NAC, ketamine + haloperidol (1.5 mg/kg), or ketamine + haloperidol + NAC daily for one week. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, and paraoxonase-1 (PON-1) activity were determined in cerebral cortex and in the rest of the brain tissue. Results indicated that: (i) treatment with only NAC had no significant effects on MDA, GSH, or PON-1 activity, but resulted in a marked decrease in nitric oxide content in both the cortex and the rest of the brain compared to the saline control group; (ii) ketamine caused a significant increase in MDA, while decreasing nitric oxide, and GSH concentrations as well as PON-1activity in both the cerebral cortex and the rest of the brain. These biochemical alterations were alleviated by NAC; (iii) in ketamine-treated mice, either clozapine or haloperidol had no significant effect on MDA or GSH levels. Nitric oxide, however, showed a significant increase by either agent. Meanwhile, PON-1 activity showed a significant increase by clozapine in the cortex but was decreased by haloperidol in both the cortex and the rest of the brain compared with the ketamine only group; (iv) NAC resulted in a significant decrease in MDA in the cortex in ketamine + haloperidol-treated mice, and markedly alleviated the decline in GSH and PON-1 activity in both the cortex and the rest of the brain tissue in ketamine + clozapine- or ketamine + haloperidol-treated groups. NACshowed variable effects on brain nitric oxide in these groups; and (v) ketamine caused neurodegeneration in the cortex and striatum changes in the form of shrunken neurons, pyknotic and apoptotic nuclei, perineuronal vacuolations, and red neurons. These pathological changes were marked after treatment with either clozapine or haloperidol but ameliorated by NAC treatment. These data indicate increased brain oxidative stress in the schizophrenia model induced by ketamine in mice and that treatment with antipsychotics impairs brain antioxidants. The study suggests a potential therapeutic benefit for NACin alleviating brain oxidative stress, lipid peroxidation, and neurodegeneration during antipsychotic drug therapy in schizophrenia.

Effects of N-acetylcysteine treatment in acute respiratory distress syndrome: A meta-analysis.

Acute respiratory distress syndrome (ARDS) is a serious complication of acute lung injury. Severe systemic inflammation is the main cause of multiple organ dysfunction and high mortality. Removal of reactive oxygen species by anti-oxidants has been applied in clinical practice. N-acetylcysteine (NAC) is the most commonly used anti-oxidant. However, the benefit of anti-oxidant therapy was not consistently demonstrated by previous studies. In the present study, a meta-analysis was performed to evaluate the effects of NAC for adult patients with ARDS. The PubMed, Cochrane and EMBASE databases were searched to retrieve all of the available randomized controlled trials (RCTs) published until October 2015. Quality evaluation of included studies was performed according to the modified Jadad scale score. The Cochrane Collaboration Review Manager 5.3 software was used to perform the meta-analysis. Five RCTs comprising 183 patients were found to be eligible for inclusion in the meta-analysis. Pooled analysis showed that NAC did not contribute to reduce short-term mortality [risk ratio (RR)=0.73; 95% confidence interval (CI): 0.50–1.07; P=0.10] or 30-day mortality (RR=0.72; 95% CI: 0.44–1.19; P=0.20) when compared with those in the control group. However, duration of intensive care unit (ICU) stay in the NAC group was shortened [weighted mean difference (WMD), −4.56; 95% CI: (−7.32 to −1.80); P=0.001]. There was no significant difference in the ratio of partial arterial oxygen pressure to the fraction of inspired oxygen between the two groups [WMD, 54.34; 95% CI: (−30.50 to 139.17); P=0.21]. No severe adverse reactions were observed in the patients included. Although the duration of ICU stay was shortened, the clinical benefits of NAC were limited for ARDS based on the present meta-analysis. As the number of included trials and patients was small, additional trials are required to provide sufficient evidence for the efficacy of NAC in ARDS.

The Effects of N-acetylcysteine in Patients with Amanita phalloides Intoxication

Objectives: Mushroom intoxication with Amanita phalloides has a high incidence throughout the world. Treatment for this intoxication is similar in different centers, but N-acetylcysteine is rarely used. In this study, we aimed to investigate the effects of N-acetylcysteine treatment in patients with Amanita phalloides intoxication. Methods: A total of 40 patients with Amanita phalloides intoxication were included in this retrospective study. The study group consisted of 24 patients who were administered N-acetylcysteine in addition to the standard regimen; the control group consisted of 16 patients who were treated only with the standard treatment. Treatment results and biochemical measurements of groups were compared. Results: According to the biochemical measurements, it was found that patients in the control group were affected more seriously by Amanita phalloides than those in the study group. The mortality rate was lower in the study group (4.4% vs. 18.7% in the control group). Conclusions: Amanita phalloides intoxication can be successfully treated with N-acetylcysteine in addition to the standard regimen. Significantly, the simplicity of administration, good tolerance, and an affordable cost make N-acetylcysteine a viable option for the treatment of Amanita phalloides intoxication. The low mortality rate presented in the study group may be ascribed to N-acetylcysteine administration.

Effect of N-acetylcysteine treatment on oxidative stress and inflammation after severe burn

Oxidative stress and inflammation generate edema in burns. The aim of our study was to assess effect of N-acetylcysteine (NAC) on oxidative stress, inflammation, fluid requirement, multiple organ dysfunction (MOD) score and vasoactive drug requirement.In this study 15 patients were on standard therapy, whereas for other 15 patients NAC was supplemented. Blood samples were taken on admission and on the next five consecutive mornings. Levels of malondialdehyde, protein sulfhydril (PSH) groups, reduced gluthation (GSH), activity of myeloperoxidase, catalase and superoxide dismutase enzymes and induced free radical generating capacity were measured as well as concentrations of TNF-α, IL-6, IL-8, and IL-10. MOD score, use of vasopressor agents and fluid utilisation were recorded daily.NAC treatment increased GSH level on days 4–5 (p<0.05) and PSH level on days 2–6 (p<0.05) compared to controls. Plasma IL-6 was lower on days 4–5 (p<0.05), IL-8 on days 4–6 (p<0.05) and IL-10 on days 4–6 (p<0.05) in NAC group. NAC group received less catecholamines than controls (p<0.01) from day 4 without significant differences in MOD score.NAC treatment is associated with a diminished oxidative stress reflected in preserved antioxidant levels, lower inflammation mirrored in lower interleukin levels and less vasopressor requirement.

Effect of N-acetylcysteine treatment on the expression of leukocyte surface markers after burn injury

Oxidative stress and inflammatory processes generate edema in burns. Treatment of consequent hypovolemia is a challenge. The aim of study was to assess if glutathione pro-drug N-acetylcysteine (NAC) can influence inflammation and fluid requirement. We also aimed to compare organ functions scores and vasoactive drug requirement. This prospective randomised study involved 28 patients with burn injury affecting more than 20% of body surface area. Fourteen patients were on standard therapy, whereas for other 14 patients NAC was supplemented. Blood samples were taken on admission and on the next five consecutive mornings. Leukocyte surface marker expressions were determined, multiple organ function scores, use of vasopressor agents and fluid requirements were recorded daily. Expression of CD11a ( p < 0.05), CD18 ( p < 0.05) and CD97 ( p < 0.01) on the granulocytes were significantly lower in the NAC treated group, similarly to lymphocyte CD 49d ( p < 0.05) and monocyte CD 49d ( p < 0.01) and CD 97 ( p < 0.05) expression. No significant difference was found in the fluid requirement between groups but patients the NAC group required less vasopressor and inotropic drugs from day 4. NAC treatment is associated with a less pronounced inflammation reflected in lower CD marker expression and vasopressor requirement.

Neuroprotective potential of N -acetylcysteine in carbofuran neurotoxicity: A biochemical and histopathological study

The present study was undertaken to evaluate biochemical markers of chronic carbofuran exposure to rats in terms of lipid peroxide and intrasynaptosomal calcium levels and to correlate them with the histopathological changes in brain regions. A significant increase in lipid peroxidation (LPO) in terms of thiobarbituric acid reactive substances (TBARS) was observed in the cerebral cortex (65%) and brain stem (33%) after carbofuran exposure. This was accompanied by a significant increase (87%) in the intracellular free-Ca2+ [Ca2+]i levels. N-acetylcysteine (NAC) administration, on the other hand, reversed the carbofuran-induced increase in LPO and [Ca2+]i. Histopathological studies of carbofuran-exposed brain revealed high frequency of pyknotic neurons in the cerebral cortex and microhaemorrhages in the brain stem. NAC supplementation to carbofuran-treated animals resulted in normalisation of the brain architecture as seen by a reduction in the number of pyknotic nuclei in the cerebral cortex. These findings indicate that increased LPO and elevated [Ca2+]i levels are involved in the development of carbofuran neurotoxicity and are eventually responsible for the pathological alterations. The study also demonstrates potential neuroprotective effect of NAC treatment in carbofuran neurotoxicity.

Effects of N-acetylcysteine Treatment on Oxidative Stress in Acetic Acid-induced Experimental Colitis in Rats

We assessed the possible protective effects of N-acetylcysteine (NAC) against toxic damage in the rat colon. Two doses of NAC (20 mg/kg and 100 mg/kg) given for 2 days and 7 days after acetic acid administration (to induce colitis) were tested. NAC was dissolved in saline and administered locally (intracolonic), systemically (intraperitoneal) or in a combination (intracolonic and intraperitoneal). Several parameters, including macroscopic and histopathological scores and myeloperoxidase, glutathione and nitric oxide concentrations were measured using standard assay procedures. Treatment with 100 mg/kg NAC for 7 days significantly decreased tissue myeloperoxidase, glutathione and nitric oxide concentrations. The 20 mg/kg dose had no protective effects. The data indicate that NAC substantially reduced the degree of colonic injury, probably by regulating free radical production and inhibiting inflammation. It may, therefore, have a role in the treatment of inflammatory bowel disease.

Protective effects of N-acetylcysteine treatment after phosgene exposure in rabbits.

We examined the effects of treatment with N-acetylcysteine (NAC) on pulmonary edema formation in isolated perfused rabbit lungs following in vivo phosgene exposure. This study focused on posttreatment intratracheal administration of NAC after exposure. Rabbits, 2 to 3 kg, were exposed to a cumulative dose of phosgene to attain a concentration x time exposure effect of 1,500 ppm/min. Lungs were perfused with Krebs-Henseleit buffer at 40 ml/min from 70 to 150 min after exposure. Pulmonary artery pressure (Ppa), tracheal pressure (Pt), and the rate of lung weight gain (LWG) were measured continuously. Perfusate concentration of peptide leukotrienes LTC4, D4, and E4 were measured every 20 min during perfusion. At the conclusion of the experiment, lung tissue was analyzed for reduced and oxidized glutathione (GSH and GSSG) and lipid peroxidation (thiobarbituric acid-reactive substances, TBARS). Exposure to phosgene significantly increased Pt, LWG, LTC4, D4, and E4, TBARS, and GSSG over time compared with controls. Compared with phosgene, intratracheal NAC lowered Ppa, LWG, LTC4, D4, and E4, TBARS, and GSSG. We conclude that NAC protected against phosgene-induced lung injury by acting as an antioxidant by maintaining protective levels of glutathione, reducing both lipid peroxidation and production of arachidonic acid metabolites.

Effect of N-acetylcysteine treatment on lung and blood superoxide dismutase activity in mercury vapors exposed rats

Effect of N-acetylcysteine treatment on lung and blood superoxide dismutase activity in mercury vapors exposed rats

No net splanchnic release of glutathione in man during N-acetylcysteine infusion.

Glutathione and amino acid concentrations were measured in arterial and hepatic vein plasma in four healthy volunteers and two patients with cirrhosis. There was no significant splanchnic efflux of glutathione (95% confidence limits, -0.501 to 0.405 mumol/min). After infusion of N-acetylcysteine (NAC) in a high dose (150 mg/kg body weight primer plus 15 mg/(h x kg BW), corresponding to treatment of acetaminophen overdose, there was no change in the splanchnic glutathione efflux (95% confidence limits, -0.531 to 0.375 mumol/min). NAC increased hepatic plasma flow rate from 0.90 +/- 0.531 min-1 to 0.97 +/- 0.11 (mean +/- SEM; p < 0.05). The effects of NAC treatment on plasma amino acids corresponded to an increased load on hepatic metabolic N conversion and transamination among nonessential amino acids. Splanchnic uptake of serine, alanine, cystine, isoleucine, and phenylalanine increased after NAC compatible with stimulated hepatic glutathione synthesis. In contrast to the rat, plasma glutathione in man probably originates mainly from extrahepatic tissues.

Lung and blood superoxide dismutase activity in mercury vapor exposed rats: effect of N-acetylcysteine treatment

Rats were exposed to mercury vapors (30 mg/m 3) for either 1 or 2 h. Histological lesions like alveolar oedema, hyaline membranes and sometimes fibrosis were observed. The lesions were more significant after 2 h of exposure, with about 50% of the animals dying within 2 weeks. The mercury level and the superoxide dismutase activity in the blood and the lungs demonstrated differences according to the time of exposure. In the animal exposed for 2 h to mercury vapors, N-acetylcysteine treatment increased survival time and the percentage of living animals. The lung superoxide dismutase was lower than in the non-treated animals indicating an antioxidant effect. Mercury levels were decreased in blood and lung, suggesting some chelating effect of N-acetylcysteine. The exact mechanism of its action must be further elucidated.