A Balance of Neuroprotective versus Neurotoxic Mechanisms in Experimental and Human Glaucoma

Abstract

Purpose: : To understand mechanisms of glaucomatous RGC loss, and to improve neuroprotective strategies. In experimental glaucoma there is up-regulation of endogenous neurotrophins such as NGF, which are not able or sufficient to provide long-lasting protection. Thus, we asked whether endogenous agents may negatively modulate neurotrophin signals. We also asked whether there are conflicting actions by each neurotrophin receptor: p75 are expressed primarily in glia, whereas neuroprotective Trk receptors are primarily in RGCs.

Methods: : Aqueous humor samples from human glaucoma or cataract patients were collected. Aqueous humor and retinas were collected from rat models of experimental glaucoma (hypertonic saline and episcleral vein cautery models). Samples were studied quantitatively for expression of α2-macroglobulin. Therapeutic studies in the episcleral vein cautery model of glaucoma applied intravitreal injections of test agents or controls at day 14 of hypertension. Measurements of the nerve fiber layer using FD-OCT were done longitudinally over 42 days of glaucoma, and at the day 42 endpoint retinas were excised and surviving RGC were quantified.

Results: : In human glaucoma and rat experimental glaucoma we detected up-regulation of a soluble protein, α2-macroglobulin, which negatively modulates NGF-TrkA action, and is directly neurotoxic to RGCs. Activated retinal glia secretes α2-macroglobulin and this requires the activity of the p75-NGF receptor. Pharmacological reduction of α2-macroglobulin reduces neurotoxicity and results in RGC survival in experimental glaucoma. A mutant form of NGF that is not neutralized by α2-macroglobulin but activates TrkA receptors promotes RGC survival in experimental glaucoma, but wild type NGF does not. Similarly, direct activation of the NGF receptor TrkA with drug-like small molecules also provides neuroprotection.

Conclusions: : In glaucomatous processes there is a balance of p75 actions in glia and TrkA actions in RGCs. Antagonists of p75 or α2-macroglobulin reduce neurotoxicity. Selective agonists of TrkA provide direct neuroprotection. This work may help to design better strategies for glaucoma and other neurodegenerative disorders.

Keywords: growth factors/growth factor receptors • cytokines/chemokines • neuroprotection