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F. Lebrun–Julien, H.U. Saragovi, A. Di Polo; Small Molecule Peptidomimetic Ligands of TrkA and P75 Neurotrophin Receptors Promote Survival of Injured Retinal Ganglion Cells in vivo . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4808.
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© ARVO (1962-2015); The Authors (2016-present)
The neurotrophins, a family of diffusible trophic molecules, play important roles in the survival of central nervous system neurons. Two classes of cell surface receptors mediate the biological effect of neurotrophins: the Trk family of receptor tyrosine kinases (TrkA, TrkB, TrkC), and the p75 receptor that binds all neurotrophins with equal affinity. The use of neurotrophins for therapeutic use has failed because of toxicity, short half–lives, pleiotropic effects and limited diffusion in target tissues. Small, and proteolytically stable ligands of neurotrophin receptors may have therapeutic potential, and receptor–selective agents can be used to unmask the role of each receptor in retinal ganglion cell (RGC) survival In this study, we tested the effect of small peptidomimetic ligands selective for TrkA or p75 on the survival of axotomized RGCs. In the adult retina, TrkA is abundantly expressed by adult RGCs, while p75 is exclusively expressed by Müller glia.
Each small molecule ligand, an agonist of TrkA (D3, 1µg/µl) and an antagonist of p75 (1 µg/µl), was injected into the vitreous chamber at the time of optic nerve transection. For analysis of neuronal survival, RGCs were backlabeled with FluoroGold and quantified on flat–mounted retinas at 1 or 2 weeks after optic nerve transection. An inactive peptimomimetic compound was used as control.
Our data demonstrate that a single intravitreal injection of D3, the TrkA receptor ligand, led to striking neuroprotection of axotomized RGCs: 80% of the total population of RGCs were alive at 1 week after axotomy (n=5), while 25% of RGCs survived at 2 weeks post–injury (n=5), a time when <10% RGCs remained in control retinas treated with inactive ligand (n=5). Of interest, the neuroprotective effect of D3 was higher than that observed with a single injection of nerve growth factor (NGF), the natural ligand of TrkA. Remarkably, a single injection of a p75 receptor antagonist led to marked RGC survival (82%, n = 5) at 1 week after optic nerve transection. Because the p75 receptor is exclusively expressed in Müller glia, this finding suggests that these cells are involved in RGC death in a p75–responsive mechanism. Possibly the in vivo use of NGF may activate Müller glia p75 and neuronal TrkA and cause confounding effects.
Our study demonstrates the neuroprotective effect of novel, small, peptimomimetic ligands of neurotrophin receptors in vivo.
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