Time-Dependent Nerve Growth Factor Signaling Changes in the Rat Retina During Optic Nerve Crush-Induced Degeneration of Retinal Ganglion Cells.

Louise Mesentier-Louro,Letizia Leocani,Pamela Rosso,Paola Tirassa,Paolo Rama,Sara De Nicolò,Marcelo Santiago,Alessandro Lambiase,Luigi De Vitis,Rosalia Mendez-Otero,Valerio Castoldi

doi:10.3390/ijms18010098

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 p75NTR enhancement. In contrast, ONC-induced reduction of TrkA, and increased proNGF were observed only at 7 and 14 dac. We propose that proNGF and p75NTR contribute 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.

Highlights

Retinal ganglion cells (RGCs) of adult mammals do not regenerate spontaneously after axonal damage; and, similar to other central neurons, injury renders them unable to reestablish functional connections, with deleterious consequences for communication even between unaffected neurons [1,2,3]
Because RGCs are dependent on the innervating target, optic-nerve crush (ONC) might be considered an appropriate model to investigate the consequences of reduced retrograde support of growth factors, including the nerve growth factor (NGF)
Several growth factors are involved in RGC degeneration following optic-nerve injury [12]; among these, NGF has proven to play a role in the survival and growth of retinal neurons during development as well as in adult life and aging [13,14,15,16,17,18,19]

Summary

Introduction

Retinal ganglion cells (RGCs) of adult mammals do not regenerate spontaneously after axonal damage; and, similar to other central neurons, injury renders them unable to reestablish functional connections, with deleterious consequences for communication even between unaffected neurons [1,2,3]. Several growth factors are involved in RGC degeneration following optic-nerve injury [12]; among these, NGF has proven to play a role in the survival and growth of retinal neurons during development as well as in adult life and aging [13,14,15,16,17,18,19]. For example, retinal NGF is increased as early as seven days after induction of ocular hypertension [20,21]. These findings suggest that the enhancement of endogenous NGF levels is not sufficient to counteract neurotoxic mechanisms and support the survival of RGC, and that other events, probably affecting NGF receptor expression, might contribute to neurodegeneration [22]

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Conclusion