|VIEIRA, GIOVANA - Purdue University|
|LOSSIE, AMY - Purdue University|
|Lay Jr, Donald|
|RADCLIFFE, JOHN - Purdue University|
|GARNER, JOSEPH - Purdue University|
Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/5/2017
Publication Date: 4/20/2017
Citation: Vieira, G.T., Lossie, A.C., Lay Jr., D.C., Radcliffe, J.S., Garner, J.P. 2017. Preventing, treating, and predicting barbering: a fundamental role for biomarkers of oxidative stress in a mouse model of trichotillomania. PLoS One. 12(4):e0175222. https://doi.org/10.137/journal.pone.0175222.
Interpretive Summary: Trichotillomania (TTM), or human compulsive hair pulling, is one of the most common psychiatric disorders, affecting approximately 3.7 million people in the United States. These patients experience pronounced psychological distress with considerable negative impact in their quality of life. Despite its high prevalence and impairment, the etiology and development of the condition are still poorly understood. Barbering behavior, which consists of hair and/or whisker plucking in mice by itself or the cagemates is a well validated model of TTM. Despite being highly common in the laboratory setting, little is known about why it occurs. Similar to TTM, barbering is more common in females, reproductive changes affect the severity of the behavior, and onset is associated with sexual maturation. Barbers show a pattern of neuropsychological biomarkers that match TTM, but are distinct. There is evidence that metabolism plays a role in barbering behavior. For instance, feeding mice with a diet that increases brain serotonin can exacerbate barbering and induce ulcerative dermatitis, a condition similar to skin picking disorder in humans. At the moment, no prescription drugs have proven to be an effective treatment for TTM. However the most effective treatment for TTM is N-acetylcysteine (NAC). NAC is known for its antioxidant properties and used mainly for acetaminophen overdose. Nevertheless, 56% of TTM patients who received NAC for 12 weeks had a reduction of symptoms compared with 16% of patients taking placebo. The first goal of this project was to investigate the efficacy of NAC in treating barbering behavior in mice. We hypothesize that the pathogenesis of barbering/TTM involves oxidative stress/damage of neurons, and that NAC is beneficial to TTM patients because of its ability to increase glutathione (an antioxidant) and consequently protect brain cells from oxidative damage. We tested this hypothesis in 32 female mice by treating half with 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. The results from the present study suggest that barbering behavior is associated with oxidative stress and the high antioxidant capacity in barbers may result from up-regulated antioxidant production in response to oxidative stress. NAC is effective in preventing and/or curing barbering probably through the improvement of glutathione synthesis in the brain, thereby preventing oxidative damage.
Technical 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 sick 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 hydroxyl-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 in the brain, thereby preventing oxidative damage.