Neuroinflammation and Neuroprotection: An Update on (Future) Neurotrophin-Related Strategies in Multiple Sclerosis Treatment

L.      De Santi; G.      Polimeni; S.      Cuzzocrea; E.      Esposito; E.      Sessa; P.      Annunziata; P.      Bramanti

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss underlying progressive clinical disability. The chronic inflammatory tissue damage involving myelin and axons is driven by autoreactive T cells and represents a key mechanism in the immunopathogenesis of MS. Over the last few years, evidence from MS and experimental models of neuroinflammation has suggested that autoimmune responses could exert neuroprotective effects through the release of neurotrophins by autoreactive T cells. Specifically, the role of the Brain-derived neurotrophic factor (BDNF) in facilitating brain tissue repair in experimental traumatic injury has been well recognized. Support for this hypothesis comes from recent studies showing that glatiramer acetate, a currently approved treatment for MS, promotes the expansion of T cell clones crossing the blood-brain barrier and releasing BDNF in situ. A small subset of autoreactive T cells expresses the high-affinity full-length receptor for BDNF (TrkB-TK) in the periphery. In MS patients, T cells show reduced susceptibility to activation-induced apoptosis, a crucial mechanism eliminating autoreactive T clones and contributing to peripheral immunologic tolerance. These findings suggest the existence of a dual effect exerted by BDNF, which not only provides neuroprotection in the CNS but also promotes the survival of autoreactive T cells through an autocrine/paracrine loop. The aim of this review is to discuss the neuroprotective effects of currently approved immunomodulatory treatments for MS and their role in regulating neurotrophin production. We will also describe novel therapeutic strategies arising from new insights on “neuroprotective autoimmunity”.

Keywords: Autoimmunity, BDNF, immunomodulatory drugs, multiple sclerosis, neuroinflammation, neuroprotection, TrkB, central nervous system (CNS), immunopathogenesis