In Experimental Glaucoma and in Optic Nerve Axotomy, Manipulation of the p75 Neurotrophin Receptor Signals Activate Neuro-Gial Mechanisms Causing RGC Neuroprotection or Increased RGC Damage

Abstract

Purpose: : To investigate the role of p75 neurotrophin receptors in neurodegeneration due to optic nerve axotomy (rapid and acute RGC death), and in glaucoma (chronic and progressive RGC death). We used functional ligands, including drug-like small molecules, that selectively target the neurotrophin receptor p75 as agonists or as antagonists. Since p75 is expressed in glia/Muller cells, a potential paracrine mechanism of action upon RGCs was investigated. Further, the correlation between neuroprotection-promoted RGC survival and retinal structural integrity was evaluated by FD-OCT in ON axotomy and in glaucoma.

Methods: : Eyes enduring optic nerve axotomy or experimental glaucoma were injected intraocularly with test agents p75 agonists or antagonists, or controls. One endpoint was the survival of retinal ganglion cells (RGCs) 14 days post-axotomy or after 42 days of glaucoma. Another endpoint was the paracrine mechanism of action by which p75 (expressed in glia/Muller cells) can regulate RGC death. The final endpoint measured the structural integrity of the retina by FD-OCT after treatments. In each rat the experimental eye was compared versus the contralateral control eye, and all experimental groups were compared to each other.

Results: : In retinas from eyes whose ON were axotomized few RGCs remained viable after 2 weeks (90% RGC death); and in eyes subjected to ocular hypertension ~30% RGCs died after 42 days. In both models, treatment with p75 antagonists delayed RGC death, whereas treatment with p75 agonists accelerated RGC death. A p75-glia paracrine mechanism of action upon RGCs was demonstrated. Neuroprotection-promoted RGC survival also results in preservation of retinal structural integrity in ON axotomy and in glaucoma.

Conclusions: : Pharmacological modulation of p75 receptors validates targeting p75 for neuroprotection strategies in traumatic optic nerve injury as well as chronic disorders. A paracrine neurotoxic mechanism is operative where p75 ligands regulate glial activity. The concept maybe expanded to other models of neurodegeneration where p75 is relevant.

Keywords: ganglion cells • retinal glia • growth factors/growth factor receptors