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Sunday, October 15, 2017 2:02:28 AM
238 - Sigma 1 receptor agonists as potential protective and reparative therapy in multiple sclerosis
R.P. Lisak, L. Nedelkoska, J.A. Benjmains Neurology, Wayne State University School of Medicine, Detroit, MI, United States
Objectives: Determine if sigma-1 receptor (S-1R) agonists can provide protection for oligodendrocytes (OL), OL precursors (OPC) and central nervous system (CNS) neurons (Neu) and promote repair. Background: S-1R are endoplasmic reticulum (ER) chaperones upregulated during ER stress, and also regulate calcium homoeostasis via inositol triphosphate at the ER-mitochondrial interface. We reported that dextromethorphan (DM), a S-1R agonist and weak NMDA receptor (NMDAR) antagonist, protects OL and OPC from toxic effects of molecules important in the pathogenesis of multiple sclerosis (MS) and increases OPC proliferation. Other groups have found inhibition of an animal model of MS by DM and another S-1R agonist. We sought to examine the potential protective and reparative effects of ANAVEX2-73, also a S-1R agonist, an NMDAR antagonist and a weak muscarinic agonist, unrelated to DM, on OL, OPC and Neu and extend our studies of DM to Neu. For both ANAVEX2-73 and DM we investigated if protection was due to agonism of S-1R.
Methods: Cell cultures containing >90% OL, OPC or Neu were prepared from neonatal rats and were incubated with staurosporine (apoptosis), glutamate (excitotoxicity), H2O2 (reactive oxygen species; ROS), quinolinic acid (inflammation) or additional medium (control) with or without DM or ANAVEX2-73 (provided by ANAVEXTM Life Sciences Corp, under the SIGMACEPTOR (R) program). Neu cultures were incubated with the same toxic molecules with/without ANAVEX2-73 or DM. We incubated OPC with ANAVEX2-73 and evaluated proliferation as well as maturation.
Results: We found that ANAVEX2-73 inhibited death of OL, OPC and Neu induced by the toxic factors and confirmed that DM also protected Neu as well as OL and OPC. Pretreatment of cultures with S-1R antagonist BD1047 inhibited the protection provided by both ANAVEX2-73 and DM. As reported earlier for DM, ANAVEX2-73 increased OPC proliferation assessed by uptake of a uridinie analog (BrdU). ANAVEX2-73 differed from our published findings with DM as it also increased maturation of OPC to more mature OL based on expression of phenotypic markers.
Conclusions: ANAVEX2-73 and DM protect OL, OPC and Neu from several toxic molecules involved in pathogenesis of MS. Protection appears to be dependent on signaling through S-1R. Both ANAVEX2-73 and DM increase OPC proliferation. ANAVEX2-73 also accelerates OPC maturation to OL. S-1R agonists could provide both protection and help with repair in MS.
Disclosure:
Robert Lisak: Grant funding from Teva, Speakers List: Teva; Consulting: Teva, Syntimmune, Celgene and RedHill Biopharm.
Liljana Nedelkoska: Nothing to disclose
Joyce Benjamins: Nothing to disclose
Research funded by the Parker Webber Chair in Neurology, Wayne State University/DMC Foundation. ANAVEX2-73 supplied by ANAVEXTM Life Sciences Corp.
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