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. 2017 Apr 20;12(4):e0175222.
doi: 10.1371/journal.pone.0175222. eCollection 2017.

Preventing, Treating, and Predicting Barbering: A Fundamental Role for Biomarkers of Oxidative Stress in a Mouse Model of Trichotillomania

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Free PMC article

Preventing, Treating, and Predicting Barbering: A Fundamental Role for Biomarkers of Oxidative Stress in a Mouse Model of Trichotillomania

Giovana de L T Vieira et al. PLoS One. .
Free PMC article

Abstract

Barbering, where a "barber" mouse plucks hair from its cagemates or itself, is both a spontaneously occurring abnormal behavior in mice and a well validated model of Trichotillomania (TTM). N-Acetylcysteine, (NAC) a cysteine derived food additive, is remarkably effective in treating TTM patients, but its mechanism of action is unknown. Reactive Oxygen Species (ROS), also known as free radicals, form as a natural byproduct of the normal metabolism of oxygen. Under normal circumstances, cells are able to defend themselves against ROS damage with antioxidant pathways. NAC is the precursor to the main antioxidant produced to defend the brain. Therefore, we hypothesized that barbering is a disease of oxidative stress, whereby ROS and/or a failure of antioxidant defenses leads to neuronal damage that induces barbering in susceptible animals. We tested this hypothesis in 32 female C57BL/6J mice by treating half with 1g/kg BW/day of NAC in their diet, and testing for protection against developing barbering behavior and curing of barbering behavior, and simultaneously testing for a panel of biomarkers of oxidative stress. NAC reduced the chance that mice would be barbers, and this effect did not differ between healthy (i.e. prevention) and affected animals (i.e. cure). Barbering animals had elevated urinary antioxidant capacity, indicative of oxidative stress, at all timepoints. Additionally, after treatment the risk of barbering increased with decreasing hydroxy-2'-deoxyguanosine (8-OHdG) levels, and with increasing glutathione (GSH) and oxidized glutathione (GSSG) levels, further indicating that barbering mice were under oxidative stress regardless of treatment with NAC. We did not find compelling evidence that urinary total antioxidant capacity, or urinary 8-OHdG, could predict response to NAC treatment. We conclude that NAC is effective in preventing and/or curing barbering at least in part by promoting GSH synthesis, thereby preventing oxidative damage.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Submitted patent: US 20130061339 A1. This does not alter our adherence to PLOS ONE policies on sharing data and materials. This article was prepared while Amy C. Lossie was employed at Purdue University. The opinions expressed in this article are the authors’ own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Figures

Fig 1
Fig 1. Total antioxidant capacity (standardized reductive capacity—mM Trolox/mM creatinine) predicts barbering status at baseline.
Total antioxidant capacity measures the activation of antioxidant defenses. All but two barbering animals showed total antioxidant capacity above the midpoint of the range observed. To show the effect of including cage as a control variable in the model, data are plotted as the observed value (0 or 100%) corrected for cage and 8-OhdG levels. (Orange squares: animals classified as non-barbers at the beginning of the study. Blue squares: animals classified as barbers at the beginning of the study).
Fig 2
Fig 2. The effect of initial barber status and NAC treatment on final barber status.
NAC treatment significantly reduced the risk of barbering after 24 weeks of treatment, both preventing onset in healthy animals, and curing animals with the behavior. (Orange bars: animals classified as non-barbers at the beginning of the study. Blue bars: animals classified as barbers at the beginning of the study. Open bars: control mice. Hashed bars: NAC treated mice).
Fig 3
Fig 3. Levels of total antioxidant capacity (standardized reductive capacity—mM Trolox/mM creatinine) of non-barbers and barbers at baseline, after NAC treatment.
NAC treated non-barbers showed higher total antioxidant capacity than control non-barbers, or NAC treated barbers at the end of the study. (Orange bars: animals classified as non-barbers at the beginning of the study. Blue bars: animals classified as barbers at the beginning of the study. Open bars: control mice. Hashed bars: NAC treated mice).

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Grant support

This work was supported in part by a grant from the Trichotillomania Learning Center (www.trich.org) to ACL and GLTV. JPG was supported in part by the Timothy Foundation, a private nonprofit fund, whose strategic funding of Trichotillomania research is inspired by the prior head and founder of TLC, Christina Pearson, in recognition of her continuing dedication to reducing the suffering of those with Trichotillomania. GLTV was partially supported by a CAPES/Fulbright Ph.D. Fellowship (fulbright.org.br/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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