Schematic representation of cell-based assays for oligodendrocyte differentiation activators.

Many small molecules with the ability to enhance OPC differentiation and remyelination in vivo have been reported to date: ARA-014418 (glycogen synthase kinase 3 (GSK3) β inhibitor) [23], 9-cis-retinoic acid (retinoid X receptor agonist) [24], rolipram (phosphodiesterase (PDE) 4 inhibitor) [25], benztropin (M1/M3 muscarinic receptor agonist) [26], clemastine (antihistamine and anticholinergic) [27], quetiapine (antipsychotic drug) [28], solifenacin (M3 inhibitor) [29], clobetasol (synthetic adrenocortical hormone), miconazole (antifungal agent) [30], tamoxifen (estrogen receptor modulator for ERα, ERβ, and GPR30) [31], U-50488 (kappa-opioid receptor agonist) [32], XAV939 (tankyrase inhibitor) [33], and VP3.15 (PDE7 and GSK3 dual inhibitor) [34]. However, most of these do not have the potential to overcome the inhibitory activities of CSPGs. We used OL1 cells cultured on aggrecan-coated substrates as a model of CSPG deposition on demyelinated plaques, and screened compounds that overcome inhibitory activity against differentiation of oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs).