title: Regeneration of lesioned entorhino-hippocampal axons in vitro by combined degradation of inhibitory proteoglycans and blockade of Nogo-66/NgR signaling.
abstract: Damaged axons do not regenerate after axotomy in the adult mammalian central nervous system (CNS). This may be due to local inhibitory factors at the site of injury, such as overexpression of chondroitin sulfate (CS) proteoglycans (CSPG), and the presence of myelin-associated inhibitors (MAI). To overcome CSPG- or myelin-induced inhibition, strategies based on extrinsic and intrinsic treatments have been developed. For example, NEP1-40 is a synthetic peptide that promotes axonal regeneration by blocking Nogo-66/NgR interaction and chondroitinase ABC (ChABC), which degrades CS, thereby also promoting axon regrowth. Here, we examined whether the combination of these complementary strategies facilitates regeneration of the lesioned entorhino-hippocampal pathway (EHP) in slice cultures. In this model, overexpressed CSPG and MAI impaired axon regrowth, which mimics regeneration failure in vivo. Both CS cleavage with ChABC and NEP1-40 strongly facilitated the regrowth of entorhinal axons after axotomy, permitting the re-establishment of synaptic contacts with target cells. However, the combined treatment did not improve the regeneration induced by ChABC alone, and the delayed treatment of ChABC, but not NEP1-40, had a less pronounced effect on axonal regrowth compared with acute treatment. These results provide insight into the development of new assays and strategies to enhance axon regeneration in injured cortical connections.
authors.affiliation: Development and Regeneration of the CNS, Department of Cell Biology, IRB-PCB, University of Barcelona, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Mingorance
authors.forename: Marta
authors.initials: M
authors.lastname: Solé
authors.forename: Vilma
authors.initials: V
authors.lastname: Munetón
authors.forename: Albert
authors.initials: A
authors.lastname: Martínez
authors.forename: Manuel
authors.initials: M
authors.lastname: Nieto-Sampedro
authors.forename: Eduardo
authors.initials: E
authors.lastname: Soriano
authors.forename: José Antonio
authors.initials: JA
authors.lastname: del Río
mesh_terms: D000818:Animals; D019771:Axotomy; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D011508:Chondroitin Sulfate Proteoglycans / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018728:Entorhinal Cortex / Q000293:injuries / Q000502:physiology*; D058851:GPI-Linked Proteins; D006624:Hippocampus / Q000293:injuries / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D009185:Myelin Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D010446:Peptide Fragments / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D058851:GPI-Linked Proteins; D009185:Myelin Proteins; C509624:NEP1-40 protein, human; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D010446:Peptide Fragments; C000603199:RTN4 protein, human; D011956:Receptors, Cell Surface; C000603201:Rtn4 protein, mouse; C419790:Rtn4r protein, mouse; D019765:Chondroitin ABC Lyase