Abstract Details

Title Dextromethorphan Protects Cells in the Oligodendroglial Lineage and Stimulates Glial Proliferation

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 164

Objective

Background BACKGROUND: DM, an NMDA receptor antagonist and sigma receptor agonist, protects neurons from glutamate excitoxicity, hypoxia and ischemia, and inhibits microglial activation, but its effects on protection of OL and OPC are unknown. It is important to protect OL to prevent demyelination and preserve axons, and to protect OPC to optimize myelination during development and remyelination following damage.

Design/Methods DESIGN/METHODS: Mixed glial cultures from newborn rat brain (Lisak, et al. 2007) were used 6-8 days after shakeoff, and contained 40% mature OL, 40% astrocytes (AS), 10% microglia (MG) and 5% OPC. Cultures were treated for 1 day with toxic agents with or without DM. For OPC, cultures were used at 1-2 days after shakeoff and contained 70% OPC, 15% AS, 15% MG and less than 1% OL. Cell death was assessed by trypan blue uptake and proliferation by BrdU uptake.

Results RESULTS: DM at 100 nM-20 microM was not toxic to OL at 1 day, with increasing toxicity at 50-100 microM. Glutamate (100 microM) killed 70% of OL; DM protected, reducing OL death to 55% at 100 nM DM and 30% at 20 microM DM, a concentration similar to that found in rat brain after oral administration of 30 mg/kg DM + quinidine sulfate (Bisaga, et al. 2008). DM at 20 microM also protected OLs from killing by NMDA, AMPA, kainate and quinolinic acid (NMDA agonist), staurosporine, and reactive oxygen species (ROS) generated by H2O2. DM did not protect against kynurenic acid (NMDA antagonist) or NO. These agents and DM were not toxic to AS or MG at the concentrations used. OPC, defined as cells expressing platelet derived growth factor receptor alpha (PDGFRa), were compared to OL. DM also protected OPC against glutamate, glutamate receptor agonists, quinolinic acid, staurosporine and ROS, but not kynurenic acid or NO, as found for OL. DM had small variable effects on glial proliferation in mature cultures in contrast to large effects in less mature cultures, where 1 microM DM stimulated proliferation of AS and MG by 2-fold, and proliferation of PDGFRa+ OPC by 4.4-fold.

Conclusions CONCLUSIONS: DM protects both OL and the more vulnerable OPC against excitotoxic and inflammatory insults, and stimulates proliferation of OPC, AS and MG in the less mature cultures. DM may be acting directly on OL or OPC via NMDA receptors or sigma receptors, or effects could be mediated indirectly by DM signaling via AS or MG.

Authors/Disclosures
Robert P. Lisak, MD, FAAN (Wayne State Univ Sch of Med, Dept of Neuro) PRESENTER	Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argnex. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG Consulting. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Third Bridge Consulting. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Clearview Consulting. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alivar Therapeutics. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ANI Pharmaceuticals. Dr. Lisak has received personal compensation in the range of $0-$499 for serving as a Consultant for Coleman Research. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Horizon. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Immunic. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Consulting. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Tedus Consulting. Dr. Lisak has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for COUR Pharma. The institution of Dr. Lisak has received research support from NINDS. The institution of Dr. Lisak has received research support from Argenx. The institution of Dr. Lisak has received research support from Ra Pharmaceuticals. Dr. Lisak has received publishing royalties from a publication relating to health care. Dr. Lisak has received publishing royalties from a publication relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Paul Matthews, MD (Imperial College, London)	No disclosure on file

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