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

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.

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

“…NAM can improve endothelial function and stabilize blood flow by preventing transient flow interruptions 93 . Endothelins are very potent vasoconstrictors that are implicated in glaucoma in humans and animal models, with endothelin receptor blockers protecting from glaucoma 19, 94–97 . NAM can reverse endothelin-mediated vasoconstriction though its inhibitory actions on ADPRC 98–100 .…”

Total Outflow Facility in Live C57BL/6 Mice of Different Age

“…Live mice and ex vivo mouse eyes are increasingly being used as glaucoma research models to better understand aqueous physiology, dissect out pathophysiology, and test new therapies [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. The mouse also offers practical advantages for studying age-related glaucoma as its lifespan and period of ageing are relatively short, spanning a period of up to 2 years [15] compared with equivalent ageing in nonhuman primates of 20-30 years [16,17,18,19].…”

Protecting retinal ganglion cells

“…A number of compounds targeting a variety of mechanisms including modulation of glutamate-induced excitotoxicity, [11][12][13][14] vascular regulation via inhibition of nitric oxide synthase 15,16 or the endothelin pathway, 17,18 oxidative stress, [19][20][21][22][23] and inhibition of glial activity 24,25 have been shown to be neuroprotective in animal models of glaucoma though few have been tested in formal clinical trials.…”