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N-acetylcysteine (NAC), an anti-oxidant, does not improve bone mechanical properties in a rat model of progressive chronic kidney disease-mineral bone disorder.

ABSTRACT: Individuals with chronic kidney disease have elevated levels of oxidative stress and are at a significantly higher risk of skeletal fracture. Advanced glycation end products (AGEs), which accumulate in bone and compromise mechanical properties, are known to be driven in part by oxidative stress. The goal of this study was to study effects of N-acetylcysteine (NAC) on reducing oxidative stress and improving various bone parameters, most specifically mechanical properties, in an animal model of progressive CKD. Male Cy/+ (CKD) rats and unaffected littermates were untreated (controls) or treated with NAC (80 mg/kg, IP) from 30 to 35 weeks of age. Endpoint measures included serum biochemistries, assessments of systemic oxidative stress, bone morphology, and mechanical properties, and AGE levels in the bone. CKD rats had the expected phenotype that included low kidney function, elevated parathyroid hormone, higher cortical porosity, and compromised mechanical properties. NAC treatment had mixed effects on oxidative stress markers, significantly reducing TBARS (a measure of lipid peroxidation) while not affecting 8-OHdG (a marker of DNA oxidation) levels. AGE levels in the bone were elevated in CKD animals and were reduced with NAC although this did not translate to a benefit in bone mechanical properties. In conclusion, NAC failed to significantly improve bone architecture/geometry/mechanical properties in our rat model of progressive CKD.

SUBMITTER: Allen MR

PROVIDER: S-EPMC7089527 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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N-acetylcysteine (NAC), an anti-oxidant, does not improve bone mechanical properties in a rat model of progressive chronic kidney disease-mineral bone disorder.

Allen Matthew R MR Wallace Joseph J McNerney Erin E Nyman Jeffry J Avin Keith K Chen Neal N Moe Sharon S

PloS one 20200323 3

Individuals with chronic kidney disease have elevated levels of oxidative stress and are at a significantly higher risk of skeletal fracture. Advanced glycation end products (AGEs), which accumulate in bone and compromise mechanical properties, are known to be driven in part by oxidative stress. The goal of this study was to study effects of N-acetylcysteine (NAC) on reducing oxidative stress and improving various bone parameters, most specifically mechanical properties, in an animal model of pr ...[more]

PMID: 32203558

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Project description:RATIONALE:Osteoporosis is common in individuals with chronic obstructive pulmonary disease. Lung-specific factors, including radiographic emphysema, independently associate with low bone mineral density in cross-sectional smoking cohorts. However, factors associated with progressive bone loss in smokers are understudied and largely unknown. OBJECTIVES:To determine the relationship between radiographic emphysema, circulating bone metabolism markers, and pulmonary function and accelerated bone mineral density loss in smokers. METHODS:Two hundred and forty male and female current and former smokers, 40 years of age or older, underwent baseline and 2-year assessments of pulmonary function, computed tomography-assessed emphysema, dual X-ray absorptiometry-measured bone mineral density, and circulating bone metabolism biomarker levels (type I collagen C-telopeptide [CTX], amino-terminal propeptide of type I procollagen [P1NP]). The association of radiographic emphysema, bone metabolism biomarker levels, and pulmonary function with accelerated hip bone mineral density loss, defined by the 75th percentile of annual hip bone mineral density decline, was determined by logistic regression modeling with adjustment for age, sex, inhaled and intermittent steroid use, active smoking, body mass index, and the presence of baseline low hip bone mineral density. RESULTS:Of those participants with accelerated hip bone mineral density loss, 22% had moderate or severe visually assessed emphysema compared with 7.2% of smokers without accelerated bone mineral density decline. Moderate to severe visually assessed emphysema (odds ratio, 2.84; 95% confidence interval, 1.01-7.98 compared with trace/mild or no visually assessed emphysema) and the 75th percentile of CTX levels (odds ratio, 2.38; 95% confidence interval, 1.20-4.72 compared with CTX levels below the 75th percentile), a marker of bone resorption, were associated with accelerated hip bone mineral density decline after adjustment for covariates and the presence of baseline low hip bone mineral density. FEV1% predicted was not associated with accelerated bone mineral density decline after adjustment for covariates. Multivariate modeling showed moderate to severe visually assessed emphysema, and the 75th percentiles of CTX were independently associated with accelerated hip bone mineral density decline after adjustment for covariates. CONCLUSIONS:Emphysema and elevated markers of bone resorption are independently associated with progressive bone mineral density loss in smokers. These clinical markers may guide targeted bone mineral density screening and monitoring in smokers at highest risk.

Project description:BackgroundMethamphetamine dependence is a significant global health concern for which there are no approved medications. The cysteine prodrug, N-acetylcysteine (NAC), has been found to ameliorate glutamate dysregulation in addiction, and to reduce craving for methamphetamine and other drugs. We evaluated the efficacy and safety of NAC as a pharmacotherapy for methamphetamine dependence.MethodsA parallel double-blind randomised placebo-controlled trial of people dependent on methamphetamine recruited from Geelong, Melbourne and Wollongong, Australia, between July 2018 and December 2019. Participants were randomised to receive either 12 weeks of oral NAC (2400 mg/day) or matched placebo, delivered as a take-home medication. The primary outcome was methamphetamine use, measured in two ways: (a) change in days of use in the past 4 weeks from baseline to weeks 4, 8 and 12, assessed using the Timeline Followback; and (b) methamphetamine-positive oral fluid samples taken weekly. Analyses were intention-to-treat and based on imputed data. Secondary outcomes were craving, severity of dependence, withdrawal severity and psychiatric symptoms (depression, suicidality, hostility and psychotic symptoms). Significance levels were p < 0.025 for primary outcomes and p < 0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257.ResultsParticipants (N = 153; 59% male, mean [SD] age 38 [8]) were randomised to placebo (n = 77) or NAC (n = 76). Both groups had a median (IQR) of 24 (15-28) days of methamphetamine use in the 4 weeks prior to baseline. Both groups significantly reduced methamphetamine use (mean [SE] reduction of 7.3 [1.2]) days for placebo, 6.8 [1.2] for NAC) but NAC did not reduce days of methamphetamine use more than placebo (group difference of 0.5 days, 97.5% CI -3.4-4.3). There was no significant effect of NAC on methamphetamine-positive oral fluid samples (placebo 79%, NAC 76%; mean difference -2.6, 97.5% CI -12.6-7.4). NAC did not significantly reduce craving, severity of dependence, withdrawal, suicidality, depression, hostility or psychotic symptoms relative to placebo. Adverse events did not differ significantly between placebo and NAC groups.InterpretationThese findings suggest that take-home oral NAC has no significant effect on methamphetamine use or most clinically related outcomes amongst people who are dependent on the drug.

Dataset Information

N-acetylcysteine (NAC), an anti-oxidant, does not improve bone mechanical properties in a rat model of progressive chronic kidney disease-mineral bone disorder.

Publications

N-acetylcysteine (NAC), an anti-oxidant, does not improve bone mechanical properties in a rat model of progressive chronic kidney disease-mineral bone disorder.

Similar Datasets

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