In the pharmaceutical panorama aimed at discovering novel therapeutic agents against multiple sclerosis (MS), sigma 1 receptor (S1R) agonists are fit-for-purpose. Indeed, their neuroprotective and neuroplastic activities within neuronal cells, where they modulate several molecular cascades involved in the onset of some central nervous system (CNS) related diseases, such as calcium homeostasis regulation, glutamate excitotoxicity inhibition and oxidative stress control, have been widely elucidated. Additionally, accumulating evidence suggests the involvement of S1R in preventing oligodendrocyte degeneration and neuroinflammation, conditions associated with MS. Relying on the strict correlation between S1R and neurodegeneration, several S1R agonists have been discovered, offering a wide spectrum of pharmaceutical agents endowed with neuroprotective properties. Despite the increasing knowledge of this molecular target, some aspects remain to be clarified, i.e. the identification of endogenous ligands, as well as its mechanism of activation. Nevertheless, the scientific community is spending its efforts to completely characterize S1R and in this context the recent publication of the three-dimensional structure, as well as the putative S1R dimerization or oligomerization, are opening the door towards a major comprehension of the S1R pathophysiological role. Throughout this chapter, we will disclose the old and new insights of this molecular target, demonstrating the high applicability of S1R in MS.
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