title: Nucleolin inhibitor GroA triggers reduction in epidermal growth factor receptor activation: Pharmacological implication for glial scarring after spinal cord injury.
abstract: Glial scarring, formed by reactive astrocytes, is one of the major impediments for regeneration after spinal cord injury (SCI). Reactive astrocytes become hypertrophic, proliferate and secrete chondroitin sulphate proteoglycans into the extracellular matrix (ECM). Many studies have demonstrated that epidermal growth factor receptors (EGFR) can mediate astrocyte reactivity after neurotrauma. Previously we showed that there is crosstalk between nucleolin and EGFR that leads to increased EGFR activation followed by increased cell proliferation. Treatment with the nucleolin inhibitor GroA (AS1411) prevented these effects in vitro and in vivo. In this study, we hypothesized that similar interactions may mediate astrogliosis after SCI. Our results demonstrate that nucleolin and EGFR interaction may play a pivotal role in mediating astrocyte proliferation and reactivity after SCI. Moreover, we demonstrate that treatment with GroA reduces EGFR activation, astrocyte proliferation and chondroitin sulphate proteoglycans secretion, therefore promoting axonal regeneration and sprouting into the lesion site. Our results identify, for the first time, a role for the interaction between nucleolin and EGFR in astrocytes after SCI, indicating that nucleolin inhibitor GroA may be used as a novel treatment after neurotrauma. A major barrier for axonal regeneration after spinal cord injury is glial scar created by reactive and proliferating astrocytes. EGFR mediate astrocyte reactivity. We showed that inhibition of nucleolin by GroA, reduces EGFR activation, which results in attenuation of astrocyte reactivity and proliferation in vivo and in vitro. EGFR, epidermal growth factor receptor.
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel. yona.goldshmit@med.monash.edu.au.|Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. yona.goldshmit@med.monash.edu.au.
authors.forename: Yona
authors.initials: Y
authors.lastname: Goldshmit
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Sari
authors.initials: S
authors.lastname: Schokoroy Trangle
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Fabian
authors.initials: F
authors.lastname: Afergan
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Iram
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel. lironit@post.tau.ac.il.
authors.forename: Ronit
authors.initials: R
authors.lastname: Pinkas-Kramarski
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide; D001253:Astrocytes / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D066246:ErbB Receptors / Q000819:agonists*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008124:Locomotion / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000473:pathology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology / Q000523:psychology; D000097796:Nucleolin
chemical_list: D052157:Aptamers, Nucleotide; D011508:Chondroitin Sulfate Proteoglycans; D066246:ErbB Receptors; D005904:Glial Fibrillary Acidic Protein; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C513936:AGRO 100; C528900:glial fibrillary astrocytic protein, mouse; C541485:EGFR protein, mouse
keywords: EGFR; GroA (AS1411); axonal regeneration; glial scar; nucleolin