Acetylcholinesterase Inhibition Promotes Retinal Vasoprotection and Increases Ocular Blood Flow in Experimental Glaucoma

Abstract

PURPOSE. A clear correlation between vascular deficits and retinal ganglion cell (RGC) loss in glaucoma has not yet been established. The question arose as to whether there is loss of inner retinal vessels following intraocular pressure (IOP) increase and, if so, whether it occurs prior to, concomitantly with, or after RGC death. We also sought to establish whether galantamine, an acetylcholinesterase inhibitor that promotes RGC survival, can protect the retinal microvasculature and enhance blood flow in experimental glaucoma. METHODS. Ocular hypertension was induced in BrownNorway rats by injection of hypertonic saline into an episcleral vein. Retinas were processed for simultaneous visualization of the retinal microvasculature and RGCs in glaucomatous and control eyes. Retinal blood flow was examined by quantitative autoradiography using N-isopropyl-p-[14 C]-iodoamphetamine. Vascular reactivity was further assessed using an in vitro retinal microvasculature preparation.RESULTS. Substantial loss of retinal capillaries was observed after induction of ocular hypertension. The onset of both microvasculature and RGC loss occurred early and proceeded at a similar rate for at least 5 weeks after the initial damage. Systemic administration of galantamine preserved microvasculature density and improved retinal blood flow in glaucomatous retinas. The vasoactive effects of galantamine on retinal microvessels occurred through activation of muscarinic acetylcholine receptors both in vitro and in vivo.CONCLUSIONS. The onset and progression of microvessel and RGC loss are concomitant in experimental glaucoma, suggesting a tight codependence between these cellular compartments. Early interventions aimed to protect the retinal microvasculature and improve blood supply are likely to be beneficial for the treatment of glaucoma.

Characteristic Patterns of Dendritic Remodeling in Early-Stage Glaucoma: Evidence from Genetically Identified Retinal Ganglion Cell Types

“…4B-E). The GFPϩ axons from control and IOP-elevated eyes also were directed to the same sublaminar zones within those targets: the lower stratum griseum superficialis of the SC (Huberman et al, 2008) and the "core" of the dorsal LGN (Huberman et al, 2008;Krahe et al, 2011;Dhande and Huberman et al, 2014). This supports the conclusion that the GFPϩ RGCs in both experimental groups consisted of the same RGC subtype: tOff-␣ RGCs ( Fig.…”

“…To investigate for anatomical changes in RGCs at early stages after elevated IOP, we began by analyzing the structure of the tOff-␣ RGCs, the RGC subtype expressing GFP in CB2-GFP mice (Table 1; Huberman et al, 2008). These RGCs have large somas, medium-sized dendritic fields, and radially organized dendrites that monostratify in the Off sublamina of the IPL (Figs.…”

“…These RGCs have large somas, medium-sized dendritic fields, and radially organized dendrites that monostratify in the Off sublamina of the IPL (Figs. 2L, 3A -C,O;Pang et al, 2003;Huberman et al, 2008). After 7 d of elevated IOP, the GFP-expressing tOff-␣ RGCs were targeted and filled, and their morphology examined.…”

“…In recent years, we discovered and characterized various transgenic mouse lines, each with 1-2 distinct RGC subtypes selectively expressing green fluorescent protein (GFP;Huberman et al, 2008Huberman et al, , 2009Osterhout et al, 2011;Rivlin-Etzion et al, 2011;Dhande et al, 2013). These mice raise the opportunity to study the detailed morphological and functional changes occurring in defined RGC populations in response to various experimental perturbations.…”

“…These mice raise the opportunity to study the detailed morphological and functional changes occurring in defined RGC populations in response to various experimental perturbations. Here we applied the "microbead occlusion" model of glaucoma Chen et al, 2011) to two of these transgenic mouse lines, which collectively label three RGC subtypes: (1) an Off-␣ RGC subtype (Huberman et al, 2008), (2) an On-direction selective RGC subtype, and (3) an On-Off-direction selective RGC subtype (Dhande et al, 2013). We also used the antibody against melanopsin protein to label and examine type 1 intrinsically photosensitive RGCs (M1 ipRGCs; Berson et al, 2010; Table 1).…”