Alpha-linolenic acid: A promising nutraceutical for the prevention of stroke

International audienceStroke is a worldwide main cause of mortality and morbidity. Most of the preventive and neuroprotective treatments identified in preclinical studies failed in clinical trials. Although there is a consensus that nutrition is important for health, its role is underestimated in stroke. Indeed an increase consumption of salt and fatty foods may promote hypertension and obesity, which are well known risk factors of stroke. In contrast it is more difficult to identify a risk factor arising from a deficiency in an essential nutrient in the diet. Western modern diets are deficient in omega-3 polyunsaturated fatty acids, which are essential for brain health. Such deficiency may constitute by itself a risk factor for stroke. Furthermore, an imbalance in the consumption of omega-6 and omega-3 progressively took place in the past 40 years leading to omega-6/omega-3 ratios that are far above the WHO healthy recommendations. A consequence of this imbalanced ratio has been the fostering of elevations in and increased prevalence of inflammatory cardiovascular diseases and obesity. In this context, this review outlines a promising therapeutic opportunity by integrating a nutritional-based approach focusing on omega-3 alpha-linolenic acid as nutraceutical to prevent the devastating damage caused by brain ischemia

Conséquences d'un dysfonctionnement astrocytaire sur la viabilité neuronale dans des modèles d'hypoxie/ischemie

Les astrocytes ont un rôle crucial dans la modulation de l'activité neuronale contrôlant la concentration extracellulaire de glutamate grâce à des transporteurs à haute affinité et secondairement dépendants de l'ATP. Dans des conditions de crise énergétique majeure comme dans l'hypoxie/ischémie (HI), la recapture de glutamate est stoppée voire même inversée, induisant une élévation de la concentration extracellulaire de glutamate. Mes travaux de thèse montrent que l'inversion de la recapture astrocytaire de glutamate induite pas le PDC dans des cultures mixtes corticales murines de neurones et d'astrocytes conduit à une mort neuronale massive, impliquant les récepteurs NMDA extrasynaptiques, une altération du potentiel membranaire mitochondrial et l'extinction de la voie de signalisation ERK 1&2. Parallélement, une privation en oxygène et en glucose (OGD, modèle HI) de 3 heures induit la mort oxydative et apoptotique s'astrocytes striataux différenciés murins ne leur permettant plus de synthétiser le glutathion, antioxydant majeur du SNC des Mammifères. Au contraire, des astrocytes indifférenciés résistent à 3h d'OGD mais présentent transitoirement un phénotype Alzheimer type II observé dans le cerveau humain périnatal ischémié. Des neurones stratiaux naïfs en coculture pendant 3 jours avec les astrocytes différenciés soumis à 3h d'OGD semblent paradoxalement plus viables qu'en coculture avec les indifférenciés. Ceci pourrait s'expliquer par une libération de glutamate par les astrocytes indifférenciés pouvant activer les R.NMDA extrasynaptiques neuronaux et déclencher la mort neuronale. Ces résultats illustrent que les astrocytes peuvent répondre différemment à une HI, modulant de façon différentielle la viabilité des neuronesAstrocytes have a crucial function in modulating neuronal activity especially in glutamatergic synapse where they tightly control transmission through sodium and secondarily ATP dependent-high affinity glutamate transporters. In hypoxic/ischemic (HI) conditions a major energetic crisis takes place and glutamate uptake has been shown to be stopped and aven reversed leading to extracellular glutamate concentration increase. My thesis results show that reverse glial glutamate uptake pharmacologically induced by PDC triggers neuronal death through extrasynaptic NMDA receptor induced calcium entry, neuronal mitochondrial membrane potential impairment and a shut off of the neurotrophic ERK 1/2 signaling pathway. This neuronal death wa rapid and necrotic. Using an oxygen and glucose deprivation model (OGD, HI model in vitro) we evidenced the oxidative and apoptotic death of differentiated (quiescent) murine striatal astrocytes 3 days after 3h-OGD. This death war correlated with a decreased capacity to synthetise glutathione the main antioxidant of the mamml CNS. By the same time, undifferentiated striatal astrocytes were resistant to 3h-OGD but changed transiently their morphology to Alzheimer type II astrocytes, a phenotype commonly observed in perinatal ischemic humain brain. Viability of striatal naïve neurons in coculture with differentiated astrocytes seemed to be higher than in coculture with undifferentiated ones. This could be explained by glutathione release from apoptotic astrocytes during the coculture, which can be neuroprotective. On the other hand a presumed glutamate release from undifferentiated astrocytes may activate extrasynaptic NMDA receptors and tigger neuronal death. These data illustrate that astrocytes may display different responses to HI insult thus conditioning neuronalAIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Alpha-linolenic acid: A promising nutraceutical for the prevention of stroke

International audienc

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study

International audienceBackground: Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.Methods: In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.Findings: Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66-6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46-0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55-3·19, p=0·53).Interpretation: Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases