diazepinylbenzoic-acid and Demyelinating-Diseases

The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS.

Topics: Aged; Alitretinoin; Animals; Benzoates; Biphenyl Compounds; Cell Differentiation; Cell Lineage; Cells, Cultured; Central Nervous System; Cerebellum; Demyelinating Diseases; Female; Gene Expression Profiling; Humans; Male; Mice; Mice, Knockout; Middle Aged; Multiple Sclerosis; Myelin Sheath; Nerve Regeneration; Neurotoxins; Oligodendroglia; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; RNA Interference; Stem Cells; Tretinoin