New antidepressive response augmentation : focus on SERT and 5-HT3 receptors blockade

Les traitements actuels de la dépression présentent une efficacité partielle et nécessitent une administration pendant plusieurs semaines avant d’obtenir un effet thérapeutique. Il est donc urgent de trouver de nouvelles stratégies antidépressives. La vortioxetine (Lu AA21004) est un nouvel antidépresseur en cours de développement. À la différence des inhibiteurs sélectifs de recapture de la sérotonine (ISRS), il est multi-cibles. Il bloque non seulement le transporteur de la sérotonine (SERT) mais aussi les récepteurs 5-HT3. Afin de caractériser les effets de ce composé et d’évaluer l'implication du blocage des récepteurs 5-HT3 dans son mécanisme d’action, plusieurs marqueurs précliniques de la réponse antidépressive ont été évalués. Nous avons utilisé des approches électrophysiologiques, immunohistochimiques, comportementales et de microdialyse chez le rat. La vortioxetine augmente la prolifération cellulaire hippocampique et induit une désensibilisation des autorécepteurs 5-HT1A dès 3 jours contre 2 à 3 semaines pour les antidépresseurs classiques. Elle induit également une importante libération de sérotonine malgré une occupation partielle du SERT. Ces effets sont liés, au moins en partie, au blocage des récepteurs 5-HT3. Nous avons ensuite montré qu’un antagoniste des récepteurs 5-HT3, l’ondansetron, à très faible dose, potentialisait l’effet d’un ISRS, la paroxetine. L’ensemble de nos données in vivo et ex vivo prouvent que le blocage des récepteurs 5-HT3 participe à l’efficacité pseudo-antidépressive de la vortioxetine. Les récepteurs 5-HT3 sont donc une cible intéressante pour améliorer l’efficacité des antidépresseurs et raccourcir leur délai d’actionTherapeutic effects of current antidepressant drugs only appear after several weeks of treatment and a significant number of patients do not respond to any treatment. Thus, more effective treatments for major depression are still needed. Vortioxetine (Lu AA21004), a novel antidepressant in development, displays effective properties in human. To the difference of selective serotonin reuptake inhibitors (SSRIs), it is a multimodal serotoninergic agent. Not only does it block the 5-HT transporter but it is also a potent 5-HT3 receptor antagonist. This current study was undertaken to characterize the effects of this compound and the role of 5-HT3 blockade. Using electrophysiological, immunohistochemical, autoradiography and behavioral approaches in rats, several pre-clinical markers of antidepressant-like response were assessed. Vortioxetine increased hippocampal cell proliferation and desensitized 5-HT1A autoreceptors from 1-3 days versus 2-3 weeks for classical antidepressants. In contrast to SSRIs, it also increased 5-HT hippocampal release with an incomplete SERT occupancy. Later effects are at least partly due to 5-HT3 receptors blockade. In parallel, we also showed that the 5-HT3 receptor antagonist ondansetron potentiated the effect of the SSRI paroxetine. Taken together, our in and ex vivo findings highlight the crucial role of 5-HT3 receptor blockade in the antidepressant-like efficacy of vortioxetine. Thus, we propose that the 5-HT3 receptors are an interesting target to improve antidepressant efficacy and reduce the therapeutic dela

Managing blood glucose levels with a hybrid closed-loop system in a patient with type 1 diabetes mellitus on enteral nutrition: A case report

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L'absorption intestinale des vitamines hydrosolubles et liposolubles en pratique clinique

International audiencePoor vitamin intake, diminished intestinal absorption or metabolism alteration can all contribute to vitamin deficiencies. Over the last twenty years, advances in molecular biology have helped to identify the majority of intestinal vitamin transporters. The purpose of this review was to summarise the state of the art in this field to help the clinicians to recognise potential clinical risk situations related to alteration of vitamin absorption. Firstly, this review detailed the intestinal absorption site and the related transporter for each vitamin. Secondly, it reported the main factors able to alter vitamin absorption. Actually, different factors, such as drugs, alcohol or intestinal resection and gastrointestinal disorders modulate vitamin absorption. Water-soluble vitamins are mainly impacted by a competitive mechanism for their transport. Fat-soluble vitamin absorption is highly dependent on the lipid absorption, and, thus, gastrointestinal disorders inducing steatorrhea are at risk of fat-soluble vitamin deficiencies. Some of the knowledge in this field was provided by in vitro studies. Future studies on the current topic are required to transpose these studies in clinical practice. We highlighted gaps in the vitamin absorption field to suggest future research directions. (C) 2017 Association pour le developpement de la recherche en nutrition (ADREN). Published by Elsevier Masson SAS. All rights reserved

Bifeprunox and aripiprazole suppress in vivo VTA dopaminergic neuronal activity via D2 and not D3 dopamine autoreceptor activation

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Deep brain stimulation as a therapeutic option for obesity: A critical review

Despite a better understanding of obesity pathophysiology, treating this disease remains a challenge. New therapeutic options are needed. Targeting the brain is a promising way, considering both the brain abnormalities in obesity and the effects of bariatric surgery on the gut-brain axis. Deep brain stimulation could be an alternative treatment for obesity since this safe and reversible neurosurgical procedure modulates neural circuits for therapeutic purposes. We aimed to provide a critical review of published clinical and preclinical studies in this field. Owing to the physiology of eating and brain alterations in people with obesity, two brain areas, namely the hypothalamus and the nucleus accumbens are putative targets. Preclinical studies with animal models of obesity showed that deep brain stimulation of hypothalamus or nucleus accumbens induces weight loss. The mechanisms of action remain to be fully elucidated. Preclinical data suggest that stimulation of nucleus accumbens reduces food intake, while stimulation of hypothalamus could increase resting energy expenditure. Clinical experience with deep brain stimulation for obesity remains limited to six patients with mixed results, but some clinical trials are ongoing. Thus, drawing clear conclusions about the effectiveness of this treatment is not yet possible, even if the results of preclinical studies are encouraging. Future clinical studies should examine its efficacy and safety, while preclinical studies could help understand its mechanisms of action. We hope that our review will provide ways to design further studies. (C) 2018 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved