The Dietary Supplement Protandim Decreases Plasma Osteopontin and Improves Markers of Oxidative Stress in Muscular Dystrophy Mdx Mice.

Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscular disorder in children, remain elusive. Oxidative damage is implicated as a pertinent factor involved in its pathogenesis. Protandim((R)) is an over-the-counter supplement with the ability to induce antioxidant enzymes. In this study we investigated whether Protandim((R)) provided benefit using surrogate markers and functional measures in the dystrophin-deficient (mdx)mouse model of DMD. Male 3-week-old mdx mice were randomized into two treatment groups: control (receiving standard rodent chow) and Protandim((R))-supplemented standard rodent chow. The diets were continued for 6-week and 6-month studies. The endpoints included the oxidative stress marker thiobarbituric acid-reactive substances (TBARS), plasma osteopontin (OPN), plasma paraoxonase (PON1) activity, H&E histology, gadolinium-enhanced magnetic resonance imaging (MRI) of leg muscle and motor functional measurements. The Protandim((R)) chow diet in mdx mice for 6 months was safe and well tolerated. After 6 months of Protandim((R)), a 48% average decrease in plasma TBARS was seen; 0.92 nmol/mg protein in controls versus 0.48 nmol/mg protein in the Protandim((R)) group (p = .006). At 6 months, plasma OPN was decreased by 57% (p = .001) in the Protandim((R))-treated mice. Protandim((R)) increased the plasma antioxidant enzyme PON1 activity by 35% (p = .018). After 6 months, the mdx mice with Protandim((R)) showed 38% less MRI signal abnormality (p = .07) than mice on control diet. In this 6-month mdx mouse study, Protandim((R)) did not significantly alter motor function nor histological criteria.

Upregulation of the creatine synthetic pathway in skeletal muscles of mature mdx mice.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular human disease caused by dystrophin deficiency. The mdx mouse lacks dystrophin protein, yet does not exhibit the debilitating DMD phenotype. Investigating compensatory mechanisms in the mdx mouse may shed new insights into modifying DMD pathogenesis. This study targets two metabolic genes, guanidinoacetate methyltransferase (GAMT) and arginine:glycine amidinotransferase (AGAT) which are required for creatine synthesis. We show that GAMT and AGAT mRNA are up-regulated 5.4- and 1.9-fold respectively in adult mdx muscle compared to C57. In addition, GAMT protein expression is up-regulated at least 2.5-fold in five different muscles of mdx vs. control. Furthermore, we find GAMT immunoreactivity in up to 80% of mature mdx muscle fibers in addition to small regenerating fibers and rare revertants; while GAMT immunoreactivity is equal to background levels in all muscle fibers of mature C57 mice. The up-regulation of the creatine synthetic pathway may help maintain muscle creatine levels and limit cellular energy failure in leaky mdx skeletal muscles. These results may help better understand the mild phenotype of the mdx mouse and may offer new treatment horizons for DMD.

Validation of the Simplified Motor Score for the prediction of brain injury outcomes after trauma.

STUDY OBJECTIVE: The Glasgow Coma Scale (GCS) score is widely used in the initial evaluation of patients with traumatic brain injury. This 15-point score, however, has been criticized as unnecessarily complex. Recently, a 3-point Simplified Motor Score (defined as obeys commands=2; localizes pain=1; withdrawals to pain or worse=0) was developed from the motor component of the GCS and was found to have a similar test performance for predicting outcomes after traumatic brain injury when compared with the GCS score as the criterion standard. The purpose of this study was to validate the Simplified Motor Score in a large heterogeneous trauma population. METHODS: This was a secondary analysis of a prospectively maintained trauma registry with consecutive trauma patients who presented to a Level I trauma center from 1995 through 2004. Test performance of the GCS and the Simplified Motor Score relative to 4 clinically relevant traumatic brain injury outcomes (emergency intubation, clinically significant brain injury, neurosurgical intervention, and mortality) was evaluated with areas under the receiver operating characteristic curves (AUCs). RESULTS: Of 21,170 patients included in the analysis, 18% underwent emergency intubation, 14% had clinically significant brain injuries, 7% underwent neurosurgical intervention, and 5% died. The AUCs for the GCS and its components ranged from 0.76 to 0.92 across the 4 outcome measures. The AUCs for the Simplified Motor Score ranged from 0.71 to 0.89, and the relative differences from the GCS AUCs ranged from 3% to 7%, with a median difference of 5%. CONCLUSION: In this external validation study, the 3-point Simplified Motor Score demonstrated similar test performance when compared with the 15-point GCS score and its components for the prediction of 4 clinically important traumatic brain injury outcomes.