ETUDE DE l’EFFET DOPANT MUSCULAIRE POTENTIEL DES ANTIDEPRESSEURS

Bien que l’effet psychotrope des antidépresseurs soit bien connu, afin de corriger les conséquences du stress et de renforcer la confiance en soi, de nombreux autres effets pharmacologiques, notamment périphériques, doivent encore être approfondis. Les antidépresseurs inhibiteurs de la recapture de la sérotonine (ISRS) peuvent avoir un effet bénéfique sur la performance physique en participant à une réparation et à une croissance plus rapides des muscles. Il a récemment été démontré que la sérotonine était impliquée dans la récupération de la force musculaire chez un modèle murin de myopathie de Duchenne (Gurel et al., 2015). Les antidépresseurs tels que les inhibiteurs sélectifs de la recapture de la sérotonine (ISRS) sont largement utilisés pour traiter divers troubles de la santé mentale, tels que la dépression modérée à sévère et l’anxiété. Les deux symptômes contribuent à l’insomnie, à la perte d’appétit, au manque de motivation et à une fatigue physique accrue. Ces symptômes peuvent nuire aux performances physiques des athlètes, en particulier de ceux qui développent des habiletés et des techniques spécifiques à un sport, reçoivent des volumes d’entraînement plus importants à différentes intensités et participent à des compétitions plus fréquentes. Par conséquent, les athlètes peuvent utiliser des médicaments qui renforcent la motivation et / ou améliorent la condition physique générale en réduisant les symptômes dépressifs. L'utilisation d'antidépresseurs n'est pas encore interdite dans les sports d'élite. Des rapports récents sur le dopage associé aux ISRS montrent une tendance croissante de son utilisation chez les athlètes en bonne santé. La consommation d'antidépresseurs chez les athlètes a augmenté dans différents sports au cours de la dernière décennie, notamment les sports d'endurance.. Notre projet doit donc permettre de caractériser les conséquences d'un traitement chronique par ISRS sur les performances physiques chez la souris et de mettre en évidence le ou les mécanismes impliqués, en particulier la variation du shunt métabolique sérotonine / kynurénine, ainsi que les modifications de biomarqueurs, variations potentiellement utilisables chez l'homme dans la lutte contre le dopage.Nous aimerions élucider notre travail de recherche dans les articles suivants:Article 1: Nous avons étudié les effets de l'exercice et de la fluoxétine seuls ou en association avec un traitement prolongé à la fluoxétine (18 mg / kg / jour) et un exercice physique d'endurance (six semaines) chez la souris mâle BalbC / j, sur tapis roulant. Nous avons ensuite évalué l'activité neurocomportementale, les marqueurs musculaires du stress oxydatif et les modifications du métabolisme du tryptophane dans les tissus plasmatiques, musculaires et cérébraux des souris BalbC / J. En général, nous nous sommes concentrés sur la vitesse aérobie la plus élevée, le temps d’endurance jusqu’à l’épuisement, la force musculaire des membres antérieurs en saisissant un mesureur de force, des tests neurocomportementaux tels que le test en champ ouvert et élevé et le labyrinthe, l’activité enzymatique mitochondriale (activité du citrate synthase et du cytochrome C oxydase) dans le muscle gastrocnémien. , marqueur de stress oxydant tel que le test DHE (Dihydroéthidium) et DCF-DA (Dichlorofluorscine diacétate).Article 2: Nous avons étudié les effets de l’exercice et de la fluoxétine seule ou les effets combinés d’un traitement prolongé à la fluoxétine (18 mg / kg / jour) et d’un exercice d’endurance physique (six semaines) chez la souris mâle BalbC / j, sur tapis roulant.As much as the psychotropic effect of antidepressants is well known, correcting the consequences of stress and boosting self-confidence, so many other pharmacological effects, peripheral in particular, remain to be deepened. Serotonin reuptake inhibitor antidepressants (SSRIs) may have a beneficial effect on physical performance by participating in faster muscle repair and growth. It has recently been shown that serotonin was involved in the recovery of muscle strength in a mouse model of Duchenne myopathy (Gurel et al., 2015).Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are widely used to treat various mental health disorders, such as moderate-to-severe depression and anxiety. Both symptoms contribute to insomnia, loss of appetite, lack of motivation and increased physical fatigue. These symptoms can impair physical performances for athletes, more specifically for those who develop sport-specific skills and techniques, receive higher training volumes at various intensities, and participate in more frequent competitions. Therefore athletes may use drugs that enhance motivation and/or improve overall fitness by reducing depressive symptoms. The use of antidepressants is not yet forbidden in elite sports. Recent reports on doping associated with SSRIs show an increasing trend of its usage among healthy athletes. The antidepressants intake among athletes has increased in different sports over the last decade, especially endurance sports. The antidepressants Bupropion and Amineptine were removed from the list of banned substances.Our project must therefore make it possible to characterize the consequences of chronic treatment with SSRIs on the physical performance in mice and to highlight the mechanism (s) involved, in particular the variation of the serotonin / kynurenine metabolic shunt, as well as the modifications of biomarkers, potentially usable variations in humans in the fight against doping.We would like to elucidate our research work in the following articles:Article 1: We studied the effects of exercise and fluoxetine alone or in combination of long-term fluoxetine treatment (18mg/kg/day) and endurance physical exercise (six weeks) in male balbC/j mice, on animal treadmill. Subsequently we evaluated neurobehavioral activity, muscle markers of oxidative stress, and changes in tryptophan metabolism in plasma, muscle and brain tissues in the BalbC/J mice. Generally we focused on the highest aerobic velocity, endurance time until exhaustion, forelimb muscle strength by gripping strength meter, neurobehavioral tests such as open field and elevated plus maze test, mitochondrial enzyme activity (Citrate synthase and cytochrome-C oxidase activity) in gastrocnemius muscle, oxidative stress marker such as DHE (Dihydroethidium) and DCF-DA (Dichlorofluorscine di-acetate)test.Article 2: We studied the effects of exercise and fluoxetine alone or combinative effects of long-term fluoxetine treatment (18mg/kg/day) and endurance physical exercise (six weeks) in male balbC/j mice, on animal treadmill. After the mentioned exercise protocol we focused on changes in tryptophan (TRP) metabolism in plasma, muscle and brain tissues in the BalbC/J mice. To confirm the metabolomic, we also studied the KP related enzyme related genes and proteins by the modern required materials and methods. We correlated the result of article1 with the metabolites level of kynurenine pathway of tryptophan metabolism. We studied the expression of transcriptor factor PGC1α level in muscle which is induced by physical exercise(Agudelo et al., 2014). PGC1α subsequently induce the expression of kynurenine aminotransferase 1 and 2 (KAT1 and KAT2) in skeletal muscles, which convert kynurenine (KYN) to kynurenic acid (KYNA). Conversion of kynurenine to kynurenic acid decrease the level of kynurenine and quinolinic acid an NMDA receptor agonist and a neurotoxic compound

Electrochemical Skin Conductance as a Marker of Painful Oxaliplatin-Induced Peripheral Neuropathy

Purpose. Oxaliplatin is a platinum compound widely used in gastrointestinal cancer treatment but produces dose-limiting peripheral neuropathy. New insights into oxaliplatin-induced peripheral neuropathy (OIPN) assessment are needed to detect more effectively this condition. In this context, we conducted Canaloxa study, a prospective preliminary clinical trial that aimed to investigate how Electrochemical Skin Conductance (ESC), a parameter used in small fiber neuropathy assessment, could be helpful in OIPN diagnosis. Methods. Cancer patients treated for at least three months with oxaliplatin and suffering from clinically OIPN were included. Electrochemical Skin Conductance, thermal thresholds, and neuropathic pain were assessed in all included patients. Results. During one year, 36 patients were included. The main result was the correlation between ESC and Neuropathic Pain Symptom Inventory score for hands (rho value = -0.69, p < 0.0001) and feet (rho value = -0.79, p < 0.0001). ESC values were lower in neuropathic patients with painful symptoms than in ones without painful symptoms (p = 0.0003 and p < 0.0001 for hands and feet, respectively). No correlation was observed between ESC and thermal thresholds. Conclusion. These preliminary data suggest that ESC could be a useful objective marker of painful oxaliplatin-induced neuropathy and could complement the use of subjective clinical scales. This study was prospectively registered on clinicaltrials.gov (NCT02827916) before patient recruitment has begun

Serotonin reuptake inhibitors improve muscle stem cell function and muscle regeneration in male mice

Abstract Serotonin reuptake inhibitor antidepressants such as fluoxetine are widely used to treat mood disorders. The mechanisms of action include an increase in extracellular level of serotonin, neurogenesis, and growth of vessels in the brain. We investigated whether fluoxetine could have broader peripheral regenerative properties. Following prolonged administration of fluoxetine in male mice, we showed that fluoxetine increases the number of muscle stem cells and muscle angiogenesis, associated with positive changes in skeletal muscle function. Fluoxetine also improved skeletal muscle regeneration after single and multiples injuries with an increased muscle stem cells pool and vessel density associated with reduced fibrotic lesions and inflammation. Mice devoid of peripheral serotonin treated with fluoxetine did not exhibit beneficial effects during muscle regeneration. Specifically, pharmacological, and genetic inactivation of the 5-HT1B subtype serotonin receptor also abolished the enhanced regenerative process induced by fluoxetine. We highlight here a regenerative property of serotonin on skeletal muscle