Multiple Sclerosis (MS) is an autoimmune demyelination disease of the central nervous system (CNS). The traditional immunotherapies so far have not been able to stop the progression of the disease. Galanin (GAL) is an inducible neuropeptide. It has diverse regulatory effects in the nervous. The expression of galanin is induced by the administration of estrogen and is increased during pregnancy in rodents. In women with MS, pregnancy has a protective effect associated with significant remission of MS symptoms during the second and third trimester. In this study, using the cuprizone (CPZ) demyelination model of MS I demonstrated that GAL has a pronounced neuroprotective effect on demyelination and remyelination, with estrogen the protection was further enhanced. Moreover, I also found differential activation of GAL receptors in the demyelination and remyelination processes. These results suggest GAL alone or combined with estrogen might introduce next generation strategies for the treatment of MS.

Multiple Sclerosis (MS) is an autoimmune demyelination disease of the central nervous system (CNS). The traditional immunotherapies so far have not been able to stop the progression of the disease. Galanin (GAL) is an inducible neuropeptide. It has diverse regulatory effects in the nervous. The expression of galanin is induced by the administration of estrogen and is increased during pregnancy in rodents. In women with MS, pregnancy has a protective effect associated with significant remission of MS symptoms during the second and third trimester. In this study, using the cuprizone (CPZ) demyelination model of MS I demonstrated that GAL has a pronounced neuroprotective effect on demyelination and remyelination, with estrogen the protection was further enhanced. Moreover, I also found differential activation of GAL receptors in the demyelination and remyelination processes. These results suggest GAL alone or combined with estrogen might introduce next generation strategies for the treatment of MS.

MS is an autoimmune neurodegenerative disease that attacks myelin, a protective sheath that covers neurons within our bodies, which may lead to numbness, tremors, issues with vision, dizziness and more. When researching the efficacy of a therapeutic in neurodegenerative diseases such as multiple sclerosis, it is crucial that the in-vivo model selected for testing allows complete and accurate data collection. Several models attempt to replicate conditions of disease, in which myelin levels have been deliberately reduced in order to study its regrowth. These models (Cuprizone and LPC injection) can be further optimized by validating a new strain of mouse, NG2-creER / Rosa-Optopatch, which will essentially express GFP+ myelin. To validate this mouse line, the following goals were pursued: Confirm NG2+ pre-OLs express GFP in the spinal cord tissue and corpus callosum in our NG2-creER mouse, confirm that myelin formed from NG2+ pre-OLs that have matured into OLs also express GFP and characterize the GFP staining pattern along with other known myelin stains (MBP, Fluoromyelin Red), and in the long run, use the NG2-creER model in MS-related targets for drug candidates as a more efficient option than traditional methods such as electron microscopy (EM). Results show that the NG2-creER mouse was successful (in both CPZ and LPC models) in showing NG2+/GFP+ cells and that these GFP+ pre-OLs matured to form GFP+ myelin, as well as showing the capability of staining myelin at a younger age than other myelin stains. / 2022-06-17T00:00:00Z

Magnetic resonance imaging (MRI) methods thought to assess myelin and axon integrity are improving the understanding of white matter diseases like multiple sclerosis (MS). This thesis improved the understanding of how microstructural tissue changes caused by various pathologies influence MRI metrics by developing and applying MRI methods in a longitudinal study using the cuprizone mouse model of MS. In vivo and ex vivo MRI measurments (T1 and T2 relaxometry, diffusion tensor imaging, and quantitative magnetization transfer imaging) were correlated with tissue measurements taken from electron microscopy images of control and cuprizone fed mice at weeks 2 and 3 of cuprizone feeding. Significant Spearman correlations included mean diffusivity vs. myelinated axon fraction (ρ=0.84), ex vivo T2 vs. myelinated axon fraction (ρ=0.68), and normalized T2-weighted signal vs. myelinated axon fraction (ρ =-0.80). Multiparametric MRI studies show promise in bridging the gap between damage detected in images and clinical status associated with MS. / May 2016

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L’imagerie par résonance magnétique (IRM) est une technique d’imagerie médicale largement utilisée pour son caractère non-invasif et pour sa capacité à explorer les tissus mous. Des techniques IRM avancées et innovantes ont été développées de manière à améliorer la spécificité du signal des techniques conventionnelles et ainsi accéder à de nouvelles informations. Un axe de recherche particulièrement important en IRM concerne la possibilité d’accéder in vivo à des informations sur la myéline. Cette dernière est un constituant majeur du système nerveux central qui assure la bonne conduction nerveuse. Sa dégradation est l’une des caractéristiques de la sclérose en plaques, qui est la première cause de handicap sévère non traumatique chez le jeune adulte. Imager la myéline par IRM demeure néanmoins un challenge du fait du temps de relaxation T2 très court des protons la constituant. Le transfert d’aimantation inhomogène (ihMT) est une technique récemment découverte qui permet d’isoler le signal de composantes macromoléculaires grâce à leurs propriétés de relaxation dipolaire, caractérisées par la constante T1D. L’objectif de ce travail de thèse a concerné la validation de la technique ihMT comme biomarqueur de la myéline et l’évaluation de la spécificité du signal pour la myéline, sur des modèles murins (souris). / Magnetic resonance imaging (MRI) is a non-invasive medical imaging technique, widely used to explore soft tissues. Advanced and innovated MRI techniques have been developed to improve the specificity of conventional MR sequences thus allowing accessing new information. A particularly important research topic concerns the ability to in vivo access myelin information. Myelin is a major component of the central nervous system responsible for a good nerve conduction. Myelin alteration occurs in multiple sclerosis, one of the main cause for young adult permanent disability. However, myelin MRI is challenged by the very short relaxation time, T2, of myelin protons. Inhomogeneous magnetization transfer (ihMT) is a recent technique, which allows assessing macromolecular tissue component by exploiting their dipolar order relaxation properties, characterized by the time constant T1D. The objective of this thesis concerned the validation of ihMT as a myelin biomarker and the evaluation of the specificity of ihMT for myelin on mouse models.

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La sclérose en plaques (SEP) est une maladie autoimmune inflammatoire et neurodégénérative du système nerveux central (SNC) chez le jeune adulte résultant d’une altération ciblée de la myéline. Les premiers symptômes de la SEP sont une détérioration cognitive, des vertiges, des douleurs, de la fatigue et une perte de la vision. En condition physiologique, les axones des neurones sont entourés par une gaine de myéline synthétisée par les oligodendrocytes permettant d’accélérer la vitesse de conduction des influx nerveux et de prévenir la mort neuronale. Le modèle expérimental le plus utilisé dans l’étude des mécanismes de la SEP est le modèle de l’encéphalomyélite autoimmune expérimentale (EAE). Après une immunisation contre la glycoprotéine oligodendrocytaire de la myéline 35-55 (MOG35-55), les lymphocytes T Cluster of differentiation (CD)4+ helper (Th)1 et Th17 auto-réactifs induisent une réponse inflammatoire aiguë à la périphérie puis migrent dans le SNC. Ils provoquent alors une réponse inflammatoire dirigée contre la myéline, avec l’intervention descellules myéloïdes. Cela aboutit à la destruction des gaines de myéline diminuant la vitesse de conduction des influx nerveux et une perte axonale, responsables des symptômes mentionnés précédemment. A l’heure actuelle, les traitements contre la SEP peuvent ralentir la progression de la paralysie et diminuer la sévérité ainsi que l’incidence des symptômes diminuant l’inflammation. En revanche, ils n’ont pas d’effets sur les formes progressives de la maladie au cours desquellesles processus neurodégénératifs s’amplifient et dominent ceux de l’inflammation. Il est donc nécessaire de trouver de nouvelles thérapies qui pourront à la fois bloquer l’inflammation et promouvoir la remyélinisation et la neurorégénération. Dans cette optique, de nouvelles cibles thérapeutiques ont émergé pour traiter la SEP : le Vasoactive Intestinal Peptide (VIP), le Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), l’orexine A, leurs récepteurs ainsi queleurs analogues. En effet, ces neuropeptides présentent des activités anti-inflammatoires et neuroprotectrices. Mes travaux de thèse ont porté sur l’étude des effets d’un agoniste de VPAC2, l’un des récepteurs de VIP et PACAP, et de l’orexine A sur les processus inflammatoires et neurodégénératifs dans le modèle d’EAE ainsi que dans le modèle toxique de la cuprizone (CPZ), induisant la mort des oligodendrocytes matures et la démyélinisation indépendamment des lymphocytes T. Après une immunisation contre la MOG35-55, un traitement systémique de court durée avec BAY55-9837, un agoniste de VPAC2, diminue la sévérité de l’EAE chronique en diminuant la réponse inflammatoire à la périphérie avec une baisse de l’activation lymphocytaire, de l’activité de présentation antigénique des cellules dendritiques et des monocytes ainsi qu’une modulation de la population des lymphocytes T régulateurs. Au niveau de la moelle épinière, l’infiltration descellules immunitaires est moindre et la proportion en microglie/macrophages est plus élevée après traitement par l’agoniste de VPAC2. De plus, BAY55-9837 diminue les processus de démyélinisation et favorise ceux de remyélinisation dans le modèle de la CPZ. En parallèle, l’administration intrapéritonéale à court terme de l’orexine A diminue drastiquement la sévérité de l’EAE chronique. Le traitement ne présente pas d’effet sur la phase d’immunisation de l’EAE mais limite la phase effectriceavec une diminution de l’infiltration des lymphocytes T CD4+, des médiateurs inflammatoires, de la démyélinisation, de l’astrogliose et de l’activation microgliale au niveau du SNC. Par contre, l’administration systémique de l’orexine A ne semble pas avoir d’effet sur les phases de démyélinisation et de remyélinisation au cours du modèle de la CPZ / Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease of the central nervous system (CNS). First MS symptoms are cognitive deterioration, dizziness, pain, fatigue and loss of vision. In physiological condition, the axons of neurons are surrounded by a myelin sheath synthesized by oligodendrocytes to accelerate the conduction velocity of nerve impulses and to prevent neuronal death. The most widely used experimental model of MS is the EAE model. After immunization against MOG35-55, self-reactive Th1 and Th17 cells induce an acute inflammatory response at the periphery and then migrate into the SNC. Then they induce an inflammatory response against myelin, with the intervention of myeloid cells. This results in the destruction of myelin sheaths decreasing the rate of conduction of nerve impulses and axonal loss, responsible for the aforementioned symptoms. Currently, MS treatments can slow the progression of paralysis and decrease the severity and the incidence of symptoms by targeting immune responses. However, these treatments have no effect on the progressive forms of the disease when the neurodegenerative processes amplify and dominate the inflammatory component. It is therefore necessary to find effective therapies that can both block inflammation and also promote remyelination and neuroregeneration.In this context, new therapeutic targets have emerged to treat MS: VIP, PACAP, orexin A, their receptors and their analogs. These neuropeptides have several effects such as anti-inflammatory and neuroprotective activities. My thesis works were focused on the effect of a VPAC2 receptor agonist, one of the three receptors of VIP and PACAP, and orexin A in inflammatory and neurodegenerative processes during MOG35-55-induced EAE model and toxic model using CPZ, which induces mature oligodendrocyte death and demyelination without the influence of lymphocytes.A short term and systemic treatment of BAY55-9837, a VPAC2 agonist, decreases chronic EAE severity with less activation of T lymphocytes and antigen presentation activities of dendritic cells and monocytes as well as Treg population modulation at the periphery. In the CNS, immune cell infiltration is reduced in VPAC2-treated mice compared to PBS-treated mice with an higher microglia/macrophage proportion. Moreover, VPAC2 agonist decreases demyelination processes and enhances remyelination during cuprizone model. In parallel, short term and intraperitoneal administration of orexin A decreases drastically the severity of chronic EAE. Orexin A treatment has no effect on immunization phase of EAE but limits effective phase with a lower infiltration of CD4+ T lymphocytes, inflammatory mediators, demyelination, astrogliosis and microglial activation in the CNS. In contrast, systemic administration of orexin A seems to have no effect during demyelination and remyelination phases in CPZ model.

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