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Regeneration of lesioned entorhino‐hippocampal axons in vitro by combined degradation of inhibitory proteoglycans and blockade of Nogo‐66/NgR signaling
Author(s) -
Mingorance Ana,
Solé Marta,
Munetón Vilma,
Martínez Albert,
NietoSampedro Manuel,
Soriano Eduardo,
Río José Antonio
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5121fje
Subject(s) - regeneration (biology) , axotomy , axon , neuroscience , inhibitory postsynaptic potential , chondroitin sulfate proteoglycan , hippocampal formation , myelin , microbiology and biotechnology , biology , chemistry , central nervous system , proteoglycan , extracellular matrix
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.