Friday, February 19, 2016 12:30 PM - 02:00 PM Hyatt Regency New Orleans - Storyville Hall
P088: Sigma-1 Receptor Agonists Inhibit Oligodendrocyte Cytotoxicity Induced by Molecules Involved in Cell Damage in Multiple Sclerosis
Background:
The sigma-1 receptor (S-1R) is an endoplasmic reticulum (ER) chaperone upregulated during ER stress; the receptor also regulates calcium homeostasis through its association with inositol triphosphate (IP3) at the ER membrane-associated mitochondrial interface. Activation of S-1R by a variety of agonists has neuroprotective effects both in vitro and in vivo. Dextromethorphan (DM) is a S-1R agonist as well as a weak N-methyl-D-aspartate receptor (NMDAR) antagonist, which in combination with quinidine sulfate is approved for treatment of pseudobulbar affect in multiple sclerosis (MS) and other neurologic diseases. We have reported that DM protects oligodendrocytes (OL) in vitro from the cytotoxic effects of staurosporine (inducer of apoptosis), glutamate (excitotoxicity), reactive oxygen species (ROS, induced by hydrogen peroxide, H202) and quinolinic acid (QA, a product of tryptophan indoleamine metabolism associated with inflammation) (Lisak et al. Glia, 2014).
Objectives:
To determine if another S-1R agonist might also have OL protective properties, which might be effective in progressive MS, we examined the effects of ANAVEX2-73 on protection of OL from these cytotoxic molecules. ANAVEX2-73 is a new clinical stage compound, which is chemically unrelated to DM, and a S-1R agonist, NMDAR antagonist, also targeting muscarinic receptors, currently in a Phase 2a trial in Alzheimer’s disease (Macfarlane et al. 2015 AAIC abstract).
Methods:
Glial cultures enriched in OL were prepared from newborn rat brain and cells identified by phenotypic markers (Lisak et al. Mult Scler, 2006). Cultures were incubated with various concentrations of ANAVEX2-73, 200 nanoM (nM)-200 microM, for 24 hours to assess cell death by trypan blue uptake. Since there was no toxicity noted at 200 nM, we then incubated cultures with staurosporine, glutamate, H2O2, QA or medium (control) and determined cell death.
Results:
ANAVEX2-73 reduced OL cell death induced by all 4 molecules by over 50%.
Conclusion:
ANAVEX2-73, which like DM is a S-1R and NMDAR antagonist but differs in other activities, protects OL from cytotoxic mechanisms involved in pathogenesis of MS lesions. Studies to determine the relative roles of S-1R agonism, NMDAR antagonism and muscarinic activities are objectives for future studies. ANAVEX2-73 and DM are small molecules that enter the central nervous system and thus have potential to provide protection of OL in MS.
Authors
Robert Lisak
Wayne State University School of Medicine
Liljana Nedelkoska
Wayne State University School of Medicine
Joyce Benjamins
Wayne State University School of Medicine
