title: Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival.
abstract: During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5-7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS.
authors: Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca "La Peraleda", s/n, 45071, Toledo, Spain.
authors: E M
authors: EM
authors: Medina-Rodríguez
authors: F J
authors: FJ
authors: Arenzana
authors: J
authors: J
authors: Pastor
authors: M
authors: M
authors: Redondo
authors: V
authors: V
authors: Palomo
authors: R
authors: R
authors: García de Sola
authors: C
authors: C
authors: Gil
authors: A
authors: A
authors: Martínez
authors: A
authors: A
authors: Bribián
authors: F
authors: F
authors: de Castro
mesh_terms: D000328:Adult; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002490:Central Nervous System / Q000378:metabolism; D002540:Cerebral Cortex / Q000201:enzymology*; D000242:Cyclic AMP / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004827:Epilepsy / Q000378:metabolism; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects*; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D000242:Cyclic AMP; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7
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