Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

Abstract

The pathophysiology of multiple sclerosis (MS) involves several components: redox, inflammatory/autoimmune, vascular, and neurodegenerative. All of them are supported by the intertwined lines of evidence, and none of them should be written off. However, the exact mechanisms of MS initiation, its development, and progression are still elusive, despite the impressive pace by which the data on MS are accumulating. In this review, we will try to integrate the current facts and concepts, focusing on the role of redox changes and various reactive species in MS. Knowing the schedule of initial changes in pathogenic factors and the key turning points, as well as understanding the redox processes involved in MS pathogenesis is the way to enable MS prevention, early treatment, and the development of therapies that target specific pathophysiological components of the heterogeneous mechanisms of MS, which could alleviate the symptoms and hopefully stop MS. Pertinent to this, we will outline (i) redox processes involved in MS initiation; (ii) the role of reactive species in inflammation; (iii) prooxidative changes responsible for neurodegeneration; and (iv) the potential of antioxidative therapy.

A Comparative Analysis of Multiple Sclerosis–Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate

“…Finally, EP and DMF are capable of providing a more direct antioxidative protection via scavenging superoxide and hydroxyl radical, which have the central place in MS-related neurodegenerative processes, such as "slow burning" of demyelinated neurons and oxidative damage directly inflicted by cytotoxic cells (5). Emerging data imply that EP might be an effective antiinflammatory agent in vivo.…”

“…The activity of DMF appears to be prevalently based on redox properties, that is, binding to thiols via Michael-type addition (3). DMF turns off thiol redox switches on T cell membrane, whereas in neurons and astrocytes, DMF targets specific thiol moieties, which leads to activation of Nrf2-controled set of antioxidative enzymes, NAD(P)H: quinine oxidoreductase 1 and glutathione-related enzymes, and downregulation of transcription factor NF-kB (2,4,5). These pharmacological strategies-targeting of redox switches to suppress T cell activity (6)(7)(8), and activation of endogenous antioxidative system instead of frequently futile application of exogenous antioxidants (9)-are rather new and hold promise of further therapeutic relevance.…”

“…We have noted recently that ethyl pyruvate (EP) might represent a DMF redox analog, and therefore could be of interest in MS treatment (5). EP forms Michael-type adducts with thiols, activates Nrf2 in astrocytes, and inhibits NF-kB-dependent transcription in different cell types, including LPS-stimulated BV2 (microglial) cells and macrophage-like RAW 264.7 cells (10-13).…”

Application of nanomedicine for crossing the blood–brain barrier: Theranostic opportunities in multiple sclerosis

“…It seems T H 1 and T H 17 cells are the main pathogenic populations in the immunopathogenesis of MS (Jadidi-Niaragh & Mirshafiey 2011b). Although there are no DC in a healthy CNS, other antigen-presenting cells (APC) like macrophages, microglia, B cells, endothelial cells and astrocytes can prime autoreactive Tcells at the disease initiation stage (Ransohoff & Engelhardt 2012;Miljković & Spasojević 2013;Yazdani et al 2013). Interestingly, it was reported that microglia and macrophages could differentiate into DC-like cells (Ponomarev et al 2005).…”

“…The cleavage of extracellular matrix by these enzymes not only damages the CNS parenchyma and BBB integrity, but also creates several protein fragments, which may act as chemoattractants and immunomodulators (Weathington et al 2006). Altogether, these events disturb BBB integrity and recruit various leukocytes into the CNS (Miljković & Spasojević 2013) (Figure 1).…”