The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J Mouse Model of Muscular Dystrophy

The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy2J/dy2J mouse model of merosin deficient congenital muscular dystrophy. The dy2J/dy2J mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy2J/dy2J mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy2J/dy2J mouse model of congenital muscular dystrophy

Environmental Enrichment Preceding Early Adulthood Methylphenidate Treatment Leads to Long Term Increase of Corticosterone and Testosterone in the Rat

Attention-deficit/hyperactivity disorder (ADD/ADHD) has been emerging as a world-wide psychiatric disorder. There appears to be an increasing rate of stimulant drug abuse, specifically methylphenidate (MPH) which is the most common treatment for ADHD, among individuals who do not meet the criteria for ADHD and particularly for cognitive enhancement among university students. However, the long term effects of exposure to MPH are unknown. Thus, in light of a developmental approach in humans, we aimed to test the effects of adolescence exposure to enriched environment (EE) followed by MPH administration during early adulthood, on reactions to stress in adulthood. Specifically, at approximate adolescence [post natal days (PND) 30–60] rats were reared in EE and were treated with MPH during early adulthood (PND 60–90). Adult (PND 90–92) rats were exposed to mild stress and starting at PND 110, the behavioral and endocrine effects of the combined drug and environmental conditions were assessed. Following adolescence EE, long term exposure to MPH led to decreased locomotor activity and increased sucrose preference. EE had a beneficial effect on PPI (attentive abilities), which was impaired by long term exposure to MPH. Finally, the interaction between EE and, exposure to MPH led to long-term elevated corticosterone and testosterone levels. In view of the marked increase in MPH consumption over the past decade, vigilance is crucial in order to prevent potential drug abuse and its long term detrimental consequences

The effect of MPH on PPI.

<p>Significant differences in PPI scores were observed. EE led to the highest PPI compared with all groups (<i>P</i><0.0001). Following MPH treatment, the EES group showed higher PPI compared with control (<i>P</i><0.0001) and stress (<i>P</i><0.001) groups. A panel of representative traces demonstrate the differences in maximal response inhibition (at pre-intensity of 69 dB) of all four groups, with and without MPH. n = 9 to 10 per group.</p

The effect of MPH on locomotor activity.

<p>A significant difference in distance (A) and velocity (B) were detected between the groups in the open field test. Rats exposed to MPH following EE showed the lowest distance and velocity. These effects were not related to differences in body weight (C). MPH treatment significantly increased freezing duration (D) compared to saline. Following EE, MPH led to the highest freezing duration. * <i>P</i><0.0001 versus control; ** a: <i>P</i><0.022, b: <i>P</i><0.008, c: <i>P</i><0.0001 versus EE saline; n = 9 to 10 per group.</p

The effect of MPH on CORT and TST levels.

<p>A significant difference in CORT (A) and TST (B) levels was observed. MPH treatment significantly increased CORT level in the EE and EES groups (* P<0.0001; ** P<0.002 compared with their respective controls). TST level was similar across all groups, while MPH treatment increased TST level in both EE and EES groups (* P<0.001; ** P<0.012 compared with their counterpart controls). n = 9 to 10 per group.</p

The effect of MPH on sucrose preference test.

<p>Considerable variation in sucrose intake was observed between the groups. While significant long term anhedonia was detected in the EE group, MPH treatment following EE significantly recovers this effect. * <i>P</i><0.019 versus control; ** <i>P</i><0.0001 versus EE saline; n = 9 to 10 per group.</p