Sigma-1 receptor agonists as potential protective therapies in multiple sclerosis

The sigma-1 receptor (σ-1R) is an endoplasmic reticulum (ER) chaperone upregulated during ER stress, and regulates calcium homeostasis. Agonists of σ-1R are neuroprotective. ANAVEX2-73, a new σ-1R agonist, is undergoing several clinical trials. We show that ANAVEX2-73 protects oligodendroglia (OL) and oligodendroglial precursors (OPC) from apoptosis, excitotoxicity, reactive oxygen species (ROS) and quinolinic acid (QA), associated with inflammation. ANAVEX2-73 stimulates OPC proliferation, but does not alter early maturation to OL. We previously reported that dextromethorphan (DM), another σ-1R agonist with a different structure, had similar effects. We now show that both DM and ANAVEX2-73 protect neurons from the four cytotoxic agents. [Display omitted] •ANAVEX2-73 is a new sigma-1 receptor (σ-1R) agonist in several clinical trials.•ANAVEX2-73 protects oligodendroglia from cytotoxic agents involved in MS pathogenesis.•ANAVEX2-73 protects oligodendroglial precursors and increases their proliferation.•Both ANAVEX2-73 and dextromethorphan, another σ-1R agonist, protect neurons.