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Therapeutic effects of VIP, PACAP, orexins and their analogs in experimental models of multiple sclerosis

Thesis

French

ID: <10670/1.69cpzd>

Abstract

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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