| Abstract No.: | A-B1064 |
| Country: | Canada |
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| Title: | REGULATION OF INJURED RETINAL GANGLION CELL DEATH VIA A P75NTR-DEPENDENT MECHANISM: POTENTIAL ROLE OF MÜLLER GLIA. |
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| Authors/Affiliations: | 2 Frédéric Lebrun-Julien*; 2 Adriana Di Polo; 1 Horacio Uri Saragovi ;
1 McGill University, Montreal, QC, Canada; 2 University of Montreal, QC, Canada
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| Content: | Objectives: The neurotrophins play important roles in the survival of central nervous system neurons. Two classes of cell surface receptors mediate the biological effect of mature neurotrophins: the Trk family of receptor tyrosine kinases and p75NTR, which binds all neurotrophins. In the adult retina, TrkA is expressed by adult retinal ganglion cells (RGCs), while p75NTR is primarily expressed by Müller glia.
Materials and Methods: Here we used small and proteolytically stable ligands of neurotrophin receptors, with receptor selective activity, to unmask the role of each receptor in RGC survival. Peptidomimetic ligands (agonist or antagonist: 1 µg/µl) were independently injected or co-injected into the vitreous chamber of adult Sprague-Dawley rats at the time of optic nerve transection. For analysis of neuronal survival, RGCs were retrogradely labeled by application of FluoroGold in the superior colliculus, the main target region of RGCs in the rodent brain. Neuronal survival was quantified at 1 or 2 weeks after nerve injury. Results: Our data demonstrate that specific activation of TrkA by a peptidomimetic agonist (D3) led to marked neuroprotection of axotomized RGCs, while intraocular administration of recombinant nerve growth factor (NGF) did not promote survival. Combination of D3 with a TrkA antagonist completely inhibited its neuroprotective effect. Remarkably, a single injection of a p75NTR receptor antagonist or a p75NTR blocking function antibody promoted robust RGC survival after axotomy. Conclusion: Collectively, our data demonstrate a neuroprotective effect of novel, small peptidomimetic ligands of neurotrophin receptors in the retina, and suggest that Müller cells are involved in the regulation of RGC death via a p75NTR-dependent mechanism.
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