Endogenous erythropoietin as part of the cytokine network in the pathogenesis of experimental autoimmune encephalomyelitis

Erythropoietin (EPO) is of great interest as a therapy for many of the central nervous system (CNS) diseases and its administration is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Endogenous EPO is induced by hypoxic/ischemic injury, but little is known about its expression in other CNS diseases. We report here that EPO expression in the spinal cord is induced in mouse models of chronic or relapsing-remitting EAE, and is prominently localized to motoneurons. We found a parallel increase of hypoxia-inducible transcription factor (HIF)-1 alpha, but not HIF-2 alpha, at the mRNA level, suggesting a possible role of non-hypoxic factors in EPO induction. EPO mRNA in the spinal cord was co-expressed with interferon (IFN)-gamma and tumor necrosis factor (TNF), and these cytokines inhibited EPO production in vitro in both neuronal and glial cells. Given the known inhibitory effect of EPO on neuroinflammation, our study indicates that EPO should be viewed as part of the inflammatory/anti-inflammatory network in MS

Application des anticorps monoclonaux a l'etude de la conformation de l'apo A-I a la surface des lipoproteines de haute densite

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Etude des effets des facteurs angiogéniques, angiopoïétines-1 et -2, sur la neurogenèse développementale et induite par une ischémie

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF

Facteurs angiogéniques et ischémie cérébrale ( rôle du vascular endothelial growth factor (VEGF) et de l'angiopoiétine-1 (Ang-1))

CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

Evaluation préclinique d'une stratégie anti-angiogenique sur la croissance des glioblastomes (effet d'une surexpression de l'angiopoïetine 2)

La thérapeutique anti-angiogénique pourrait être appliquée aux glioblastomes (GBM), caractérisés par une forte vascularisation et agressivité. Les stratégies actuelles bloquent majoritairement l effet biologique du VEGF. Nous avons cherché à optimiser cette stratégie en l associant à une surexpression d Ang2, un facteur angiogénique qui, en absence de VEGF, induit une régression vasculaire. Nous avons ainsi montré, sur un modèle orthotopique de GBM chez le rat, qu un apport d Ang2 est tout aussi efficace qu un traitement (Sunitinib) bloquant la signalisation du VEGF. En effet, cet apport d Ang2 conduit à une réduction significative du volume tumoral (80%) et à une augmentation du temps de survie des animaux (70%). En revanche, un traitement combiné associant le Sunitinib et une surexpression d Ang2 n a pas d efficacité supérieure à celle de chacun des traitements. En utilisant l immunohistologie et plusieurs modalités de l IRM, nous avons aussi montré que l effet vasculaire d Ang2 dépend de sa concentration : un effet déstabilisant est observé avec une faible concentration d Ang2, mais une forte concentration d Ang2 conduit à un remodelage morphologique des vaisseaux, à des modifications hémodynamiques et conduit à un blocage des effets du Sunitinib. Nos résultats suggèrent qu une stratégie ciblant le remodelage des vaisseaux préexistants dans la tumeur est tout aussi efficace qu une stratégie bloquant la formation des néovaisseaux. Cette étude montre également l intérêt de l IRM qui, par ses multimodalités, permet un suivi longitudinal de la vascularisation et de la croissance tumorale, nécessaires pour évaluer l efficacité de nouvelles thérapeutiques anti-angiogéniques.The anti-angiogenic therapy could be efficient against Glioblastoma (GBM), characterized by a strong vascularisation and aggressiveness. The current strategies mainly block the biological effect of VEGF. We sought to optimize this strategy by associating it with a surexpression of Ang2, an angiogenic factor, which, in absence of VEGF, induces a vascular regression. We thus showed, on an orthotopic model of GBM in the rat, that an application of Ang2 is as effective as a treatment blocking the VEGF signalling pathway (Sunitinib). Indeed, a chronic expression of Ang2 in tumor cells led to a significant reduction of tumor volume (80%) and to an increase in animal survival (70%). On the other hand, a combined treatment (Sunitinib and Ang2) is no more efficient than each treatment. By using immunohistology and several MRI methods, we also showed that Ang2-derived vascular effects depend on its concentration: a destabilizing effect is observed with a weak concentration of Ang2, but a strong concentration of Ang2 leads to a morphological vascular remodelling, hemodynamic modifications and a blockade of the anti-vascular effects of Sunitinib treatment.Our results suggest that a vascular strategy targeting the remodelling of the tumor pre-existing vessels is as effective as a strategy targeting neovessels. This study also shows the interest of MRI, which, thanks to its multimodalities, allows a longitudinal follow-up of the vascularisation in relation with tumor growth, necessary to evaluate the effectiveness of novel anti-angiogenic therapeutics.CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

Implication du système EPO/EPOR dans la croissance des glioblastomes et l'efficacité des traitements par chimiothérapie et radiothérapie (études in vitro et in vivo)

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF

Brain ischemic injury in rodents: the protective effect of EPO.

CERVOXYInternational audienc

Comparison of rodent and human astrocytes sensitivity and responses after irradiation

CERVOXYInternational audienc

Comparison of the sensitivity of murine and human astrocytes after different modalities of irradiation

CERVOXYInternational audienc

Crosstalk between HIF-1 and ROCK pathways in neuronal differentiation of mesenchymal stem cells, neurospheres and in PC12 neurite outgrowth.

This study demonstrates that the Rho-kinase (ROCK) inhibitor, Y-27632, potentiates not only the effect of cobalt chloride (CoCl(2)) but also that of deferoxamine, another HIF-1 inducer, on mesenchymal stem cell (MSC) neuronal differentiation. HIF-1 is essential for CoCl(2)+/-Y-27632-induced MSC neuronal differentiation, since agents inhibiting HIF-1 abolish the changes of morphology and cell cycle arrest-related gene or protein expressions (p21, cyclin D1) and the increase of neuronal marker expressions (Tuj1, NSE). Y-27632 potentiates the CoCl(2)-induced decrease of cyclin D1 and nestin expressions, the increase of HIF-1 activation and EPO expression, and decreases pVHL expression. Interestingly, CoCl(2) decreases RhoA expression, an effect potentiated by Y-27632, revealing crosstalk between HIF-1 and RhoA/ROCK pathways. Moreover, we demonstrate a synergistic effect of CoCl(2) and Y-27632 on neurosphere differentiation into neurons and PC12 neurite outgrowth underlining that a co-treatment targeting both HIF-1 and ROCK pathways might be relevant to differentiate stem cells into neurons