Poster Session - Abstract # 2

Dose Effect of Thyroid Hormone on Myelin Damage and Myelin Repair

Rashmi B. Binjawadagi, Hiroko Kobayashi, Ethan Christ, Jenna Williams, Meredith Hartley

Department of Chemistry, University of Kansas, Lawrence, KS, USA

Multiple sclerosis (MS) is an autoimmune chronic inflammatory neurodegenerative disease of central nervous system (CNS), associated with impaired motor ability in the affected patients.  Demyelination of axons in the CNS is a main characteristic of MS.  Thyroid hormone (TH) plays an important role in oligodendrogenesis and myelination during developmental stage in human CNS.  Although TH promotes OPC differentiation, it is also known to block formation of OPCs from NSCs.  Neural stem cells (NSCs) in the subventricular zone (SVZ) of the brain can differentiate into neurons, oligodendrocyte precursor cells (OPCs), and astrocytes.  Higher levels of TH switch NSCs towards neuronal lineage and block differentiation into OPCs.  This opposing role of TH in neurodevelopmental processes like migration, differentiation, and myelination are regulated by spatial and temporal action of TH.  During myelin damage, the role of elevated TH on OPCs is not well elucidated.  We are hypothesizing that a moderate increase in TH can repair demyelination by improving the OPC differentiation and promote myelination without disturbing the NSC-OPC pool.  This can be achieved initially by identifying a tolerated dose of TH that increases OPC differentiation leading to remyelination using induced conditional knock out Myrf^fl/fl; Plp1-CreERT (iCKO-Myrf) genetic mouse model, followed by mapping the effects of TH on NSCs and OPCs in the presence of induced myelin damage.  To test our hypothesis, we performed a 10-week (demyelination) experiment with different doses of thyroid hormone T3 (6 ppm,0.6 ppm, 0.2ppm, 0.06ppm, 0.02ppm) and 4ppm T4/T3 treatments along with 0.4 ppm sobetirome as a positive control, using iCKO-Myrf mouse model.  Weekly body weights and disease scores analyses indicated that 0.6 ppm, 0.2ppm, and 0.06ppm doses of TH were well tolerated.  Currently we are analyzing the brain and spinal cord samples collected from this study by immunofluorescence to determine the effect of treatments on the NSC and OPC populations and OPC differentiation.  In iCKO-Myrf model, demyelination and remyelination phases distinctly correlate with the motor ability.  Therefore, to further evaluate the effects of the selected three doses of TH in iCKO-Myrf mice experiencing demyelination (10-14 weeks) followed by remyelination (18-24 weeks), we are conducting a 24-week experiment. Along with weekly body weights and scores, motor ability (bi-weekly behavioral) tests using a rotarod and challenge ladder will be conducted.  Thus, these studies are expected to aid in understanding the role of TH during myelin damage and myelin repair.