Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma

• Published in: Neurobiology of disease Vol. 71; pp. 44 - 52
• Main Authors: Howell, Gareth R, MacNicoll, Katharine H, Braine, Catherine E, Soto, Ileana, Macalinao, Danilo G, Sousa, Gregory L, John, Simon W.M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2014; Elsevier
• Subjects: Animals; Astrocytes - metabolism; Complement; Complement C1q - metabolism; DBA/2J; Disease Models, Animal; Endothelial Cells - metabolism; Endothelin; Endothelin A Receptor Antagonists - therapeutic use; Endothelin-2 - metabolism; Glaucoma; Glaucoma - complications; Glaucoma - pathology; Humans; Mice; Mice, Inbred DBA; Nerve Degeneration - etiology; Nerve Degeneration - pathology; Nerve Degeneration - therapy; Neurology; Optic nerve head; Pyrimidines - therapeutic use; Receptor, Endothelin A - metabolism; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - pathology; Sulfonamides - metabolism; Sulfonamides - therapeutic use; Glaucoma; Optic nerve head; Complement; Endothelin; DBA/2J
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2014.07.016

Abstract The endothelin system is implicated in various human and animal glaucomas. Targeting the endothelin system has great promise as a treatment for human glaucoma, but the cell types involved and the exact mechanisms of action are not clearly elucidated. Here, we report a detailed characterization of the endothelin system in specific cell types of the optic nerve head (ONH) during glaucoma in DBA/2J mice. First, we show that key components of the endothelin system are expressed in multiple cell types. We discover that endothelin 2 (EDN2) is expressed in astrocytes as well as microglia/monocytes in the ONH. The endothelin receptor type A ( Ednra ) is expressed in vascular endothelial cells, while the endothelin receptor type B ( Ednrb ) receptor is expressed in ONH astrocytes. Second, we show that Macitentan treatment protects from glaucoma. Macitentan is a novel, orally administered, dual endothelin receptor antagonist with greater affinity, efficacy and safety than previous antagonists. Finally, we test the combinatorial effect of targeting both the endothelin and complement systems as a treatment for glaucoma. Similar to endothelin, the complement system is implicated in a variety of human and animal glaucomas, and has great promise as a treatment target. We discovered that combined targeting of the endothelin (Bosentan) and complement ( C1qa mutation) systems is profoundly protective. Remarkably, 80% of DBA/2J eyes subjected to this combined inhibition developed no detectable glaucoma. This opens an exciting new avenue for neuroprotection in glaucoma.