INVOLVEMENT OF HUR CASCADE IN MULTIPLE SCLEROSIS: FOCUS ON THE EFFECT OF DIMETHYL FUMARATE AND OCRELIZUMAB

The present PhD thesis collects all the works related to my research activity carried out at the Department of Drug Sciences, Pharmacology section, University of Pavia. My primary project, in collaboration with the Multiple Sclerosis Centre directed by Dr. Roberto Bergamaschi (at IRCCS National Neurological Institute “C. Mondino” of Pavia), mainly focused on the investigation of a novel molecular mechanism of action of dimethyl fumarate and ocrelizumab, two effective treatments for Relapsing Multiple Sclerosis, a complex neurodegenerative disorder of the central nervous system (CNS), characterized by chronic inflammation, demyelination, and irreversible axonal injury. Besides my primary project, I was also involved in other projects. Specifically, given that gut microbiota (GM) is emerging as a key player in the pathogenesis of several diseases, I carried out a literature search to explore the contribution of GM in several diseases' development/progression, including multiple sclerosis itself, Parkinson’s disease (PD), ocular disorders, neuropsychiatric (especially depression), and metabolic disorders [specifically non-alcoholic fatty liver disease (NAFLD)]. In this regard, I summarized the main strategies useful for reinstating a correct balanced intestinal flora (including, probiotics, prebiotics, FMT, and dietary interventions), which could represent a pioneering approach to prevent and/or help treating these disorders. An additional player in disease pathogenesis is represented by RNA binding proteins (RBPs), a topic of great interest to my research group. Therefore, in this context, I also wrote a review focusing on the possible role of RBPs in cellular senescence, also underlying their dysregulation in the pathogenesis and progression of the main age-related diseases, namely Alzheimer’s disease (AD), PD, Huntington’s disease, type 2 diabetes, and osteoporosis. Besides this review, I also participated in some collaborative research projects to investigate the implication of specific RBPs, namely HuR and HuD, and their targets in some neurodegenerative disorders. In this respect, I took part in a collaborative project with the group of Prof. Collina (Department of Drug Sciences, Medicinal Chemistry Section at the University of Pavia), in which we investigated, at cellular level, the effect of two specific compounds, namely folic acid (FA) and (R)-aloesaponol-III 8-methyl ether (ASME) on HuD expression. Moreover, I was also involved in another project addressed to investigate the capability of troxerutin to be a successful preventive treatment during the early phases of a relevant neurodegenerative disease, diabetic retinopathy, one of the most common complications of diabetes mellitus and the leading cause of impaired vision in the working-age population. Since oxidative stress (OS) is considered a major trigger of senescence, as well as an early driver of several age-related diseases including AD, I wrote two reviews focused on some potential antioxidant molecules (including enzymes, mitochondria-targeting compounds, vitamins, carotenoids, organosulfur compounds, minerals, flavonoids, and non-flavonoids) useful in counteracting OS in aging and AD. The endogenous antioxidant defense plays a big part also in the pathogenesis of NAFLD, a common metabolic disorder characterized by a disrupted lipid metabolism, fat accumulation, and lipid droplet formation. Within this context, I was also involved in a collaborative research activity, with the group of Proff. Vairetti and Ferrigno (Department of Internal Medicine and Therapeutics at the University of Pavia), aimed to explore the expression of HuR and some selected down-stream targets (i.e. manganese-dependent superoxide dismutase and heme oxygenase-1) in a methionine-choline deficient animal model of NAFLD, which is characterized by elevated hepatic OS.