title: Salubrinal inhibits the expression of proteoglycans and favors neurite outgrowth from cortical neurons in vitro.
abstract: After CNS injury, astrocytes and mesenchymal cells attempt to restore the disrupted glia limitans by secreting proteoglycans and extracellular matrix proteins (ECMs), forming the so-called glial scar. Although the glial scar is important in sealing the lesion, it is also a physical and functional barrier that prevents axonal regeneration. The synthesis of secretory proteins in the RER is under the control of the initiation factor of translation eIF2α. Inhibiting the synthesis of secretory proteins by increasing the phosphorylation of eIF2α, might be a pharmacologically efficient way of reducing proteoglycans and other profibrotic proteins present in the glial scar. Salubrinal, a neuroprotective drug, decreased the expression and secretion of proteoglycans and other profibrotic proteins induced by EGF or TGFβ, maintaining eIF2α phosphorylated. Besides, Salubrinal also reduced the transcription of proteoglycans and other profibrotic proteins, suggesting that it induced the degradation of non-translated mRNA. In a model in vitro of the glial scar, cortical neurons grown on cocultures of astrocytes and fibroblasts with TGFβ treated with Salubrinal, showed increased neurite outgrowth compared to untreated cells. Our results suggest that Salubrinal may be considered of therapeutic value facilitating axonal regeneration, by reducing overproduction and secretion of proteoglycans and profibrotic protein inhibitors of axonal growth.
authors.affiliation: Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain; Laboratorio de Plasticidad Neural, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071 Toledo, Spain.
authors.forename: M Asunción
authors.initials: MA
authors.lastname: Barreda-Manso
authors.affiliation: Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Yanguas-Casás
authors.affiliation: Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain; Laboratorio de Plasticidad Neural, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071 Toledo, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Nieto-Sampedro
authors.affiliation: Laboratorio de Plasticidad Neural, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071 Toledo, Spain. Electronic address: lromeroramirez@sescam.jccm.es.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Romero-Ramírez
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000293:injuries / Q000502:physiology*; D002934:Cinnamates / Q000494:pharmacology*; D018920:Coculture Techniques; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010766:Phosphorylation; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011509:Proteoglycans / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D002934:Cinnamates; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C496827:salubrinal; D017346:Protein Serine-Threonine Kinases; C531557:eIF2alpha kinase, mouse; D013890:Thiourea
keywords: Astrocytes; CSPG; Neurite outgrowth; Salubrinal; Translation attenuation; mRNA degradation