title: Time-Dependent Nerve Growth Factor Signaling Changes in the Rat Retina During Optic Nerve Crush-Induced Degeneration of Retinal Ganglion Cells.
abstract: Nerve growth factor (NGF) is suggested to be neuroprotective after nerve injury; however, retinal ganglion cells (RGC) degenerate following optic-nerve crush (ONC), even in the presence of increased levels of endogenous NGF. To further investigate this apparently paradoxical condition, a time-course study was performed to evaluate the effects of unilateral ONC on NGF expression and signaling in the adult retina. Visually evoked potential and immunofluorescence staining were used to assess axonal damage and RGC loss. The levels of NGF, proNGF, p75NTR, TrkA and GFAP and the activation of several intracellular pathways were analyzed at 1, 3, 7 and 14 days after crush (dac) by ELISA/Western Blot and PathScan intracellular signaling array. The progressive RGC loss and nerve impairment featured an early and sustained activation of apoptotic pathways; and GFAP and p75NTRenhancement. In contrast, ONC-induced reduction of TrkA, and increased proNGF were observed only at 7 and 14 dac. We propose that proNGF and p75NTRcontribute to exacerbate retinal degeneration by further stimulating apoptosis during the second week after injury, and thus hamper the neuroprotective effect of the endogenous NGF. These findings might aid in identifying effective treatment windows for NGF-based strategies to counteract retinal and/or optic-nerve degeneration.
authors.affiliation: San Raffaele Scientific Institute, Division of Neuroscience, Eye Repair Unit, 20132 Milan, Italy. lmesentier@biof.ufrj.br.|Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil. lmesentier@biof.ufrj.br.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Mesentier-Louro
authors.affiliation: National Research Council (CNR) Institute of Cell Biology & Neurobiology (IBCN), 00143 Rome, Italy. saradenicolo@libero.it.
authors.forename: Sara
authors.initials: S
authors.lastname: De Nicolò
authors.affiliation: National Research Council (CNR) Institute of Cell Biology & Neurobiology (IBCN), 00143 Rome, Italy. pam.rosso@gmail.com.|Department of Science, University Roma Tre, 00146 Rome, Italy. pam.rosso@gmail.com.
authors.forename: Pamela
authors.initials: P
authors.lastname: Rosso
authors.affiliation: San Raffaele Scientific Institute, Division of Neuroscience, Eye Repair Unit, 20132 Milan, Italy. l.devitis@studenti.unisr.it.
authors.forename: Luigi A
authors.initials: LA
authors.lastname: De Vitis
authors.affiliation: San Raffaele Scientific Institute, Division of Neuroscience, Institute of Experimental Neurology, 20132 Milan, Italy. castoldi.valerio@hsr.it.
authors.forename: Valerio
authors.initials: V
authors.lastname: Castoldi
authors.affiliation: San Raffaele Scientific Institute, Division of Neuroscience, Institute of Experimental Neurology, 20132 Milan, Italy. leocani.letizia@hsr.it.
authors.forename: Letizia
authors.initials: L
authors.lastname: Leocani
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil. rmotero@biof.ufrj.br.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Mendez-Otero
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil. marcelo.santiago@biof.ufrj.br.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Santiago
authors.affiliation: National Research Council (CNR) Institute of Cell Biology & Neurobiology (IBCN), 00143 Rome, Italy. paola.tirassa@cnr.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Tirassa
authors.affiliation: San Raffaele Scientific Institute, Division of Neuroscience, Eye Repair Unit, 20132 Milan, Italy. rama.paolo@hsr.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rama
authors.affiliation: Department of Sense Organs-Section of Ophthalmology, University of Rome "Sapienza", 00185 Rome, Italy. alessandro.lambiase@uniroma1.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lambiase
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D005074:Evoked Potentials, Visual / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D009409:Nerve Crush; D020932:Nerve Growth Factor / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020221:Optic Nerve Injuries / Q000150:complications*; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D020917:Receptor, trkA / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000503:physiopathology; D012162:Retinal Degeneration / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: C000614142:Gfap protein, rat; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D017475:Receptors, Nerve Growth Factor; C514218:pro-nerve growth factor, rat; D020932:Nerve Growth Factor; D020917:Receptor, trkA
keywords: glaucoma; nerve growth factor; optic-nerve crush; retinal ganglion cells