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

Schematic diagram of experimental design and procedures.

<p>Schematic diagram of experimental design and procedures.</p

Dog training alleviates PTSD symptomatology by emotional and attentional regulation

Background: Post-Traumatic Stress Disorder (PTSD) symptoms include re-experiencing, avoidance, hyperarousal, and cognitive deficits, reflecting both emotional and cognitive dysregulation. In recent years, non-pharmacological approaches and specifically animal-assisted therapy have been shown to be beneficial for a variety of disorders such as Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, and PTSD. However, little is mentioned in the literature about the reciprocal effects of the animal–human interaction. Objective: To evaluate the effects of a one-year dog training programme on PTSD symptomatology in youngsters with PTSD and on dogs’ behaviour. Methods: Fifty-three adolescents, previously exposed to interpersonal trauma, were clinically diagnosed with PTSD and assigned to a dog-training programme group (n = 30) and a control group (n = 23) that engaged in other training programmes (e.g. cooking, hairstyling, etc.). Both groups were evaluated at baseline and following 12-months by The Clinician-Administered PTSD Scale for DSM-5 in Children and Adolescents (CAPS-CA-5) and Beck-Depression Inventory (BDI). Additionally, we physiologically measured both emotional and attention dysregulation. Results: Post-12-months training, a significant alleviation of PTSD symptomatology accompanied by lower depression severity was observed in the dog-training group, compared with a insignificant recovery in the control group. Furthermore, improved emotional and attentional regulation was observed in the dog-training group. Measuring the dogs’ behaviour revealed increased anxiety and decreased selective attention performance, which was inversely correlated with the beneficial effects observed in the dog-training programme group. Conclusions: Our findings emphasize the role of emotional and attentional regulations on the dog–handler interface, as evidence-based support for the beneficial effects of the dog-training programme, as either a non-pharmacological intervention or as complementary to anti-depressants treatment of PTSD. Though pharmacological treatments increase the patients’ well-being by treating certain PTSD symptoms, our suggested dog-training programme seems to influence the PTSD diagnostic status, thus may be implemented in civilians and veterans with PTSD

Methylphenidate and environmental enrichment ameliorate the deleterious effects of prenatal stress on attention functioning

<div><p></p><p>Either pre- or post-natal environmental factors seem to play a key role in brain and behavioral development and to exert long-term effects. Increasing evidence suggests that exposure to prenatal stress (PS) leads to motor and learning deficits and elevated anxiety, while enriched environment (EE) shows protective effects. The dopaminergic system is also sensitive to environmental life circumstances and affects attention functioning, which serves as the preliminary gate to cognitive processes. However, the effects of methylphenidate (MPH) on the dopaminergic system and attentional functioning, in the context of these life experiences, remain unclear. Therefore, we aimed to examine the effects of EE or PS on distinct types of attention, along with possible effects of MPH exposure. We found that PS impaired selective attention as well as partial sustained attention, while EE had beneficial effects. Both EE and MPH ameliorated the deleterious effects of PS on attention functioning. Considering the possible psychostimulant effect of MPH, we examined both anxiety-like behavior as well as motor learning. We found that PS had a clear anxiogenic effect, whereas EE had an anxiolytic effect. Nevertheless, the treatment with both MPH and/or EE recovered the deleterious effects of PS. In the motor-learning task, the PS group showed superior performance while MPH led to impaired motor learning. Performance decrements were prevented in both the PS + MPH and EE + MPH groups. This study provides evidence that peripubertal exposure to EE (by providing enhanced sensory, motor, and social opportunities) or MPH treatments might be an optional therapeutic intervention in preventing the PS long-term adverse consequences.</p></div