Complement mediated apoptosis leads to the loss of retinal ganglion cells in animal model of glaucoma

Abstract

This study investigated the role of complement in the protection of retinal ganglion cells (RGCs) in chronic ocular hypertension model of glaucoma. Intraocular pressure (IOP) was elevated in the right eye of Lewis rats by laser photocoagulation (two treatments, 7 days apart) of episcleral and limbal veins. Left eye did not receive laser treatment and served as control. Animals were injected with cobra venom factor every fifth day starting day 7 after first laser, to deplete the complement system. Animals were sacrificed at six week post-laser. Levels of C3 split products and membrane attack complex (MAC) were elevated in the retina of eyes with increased IOP and complement depletion reduced the loss of Brn3a+ RGCs accompanied by decreased expression of GFAP and reduced MAC deposition. In complement depleted rats with increased IOP, reduced TUNEL+ cells in ganglion cell layer, and decreased levels of active caspase-8 and active caspase-9 was observed compared to PBS treated complement sufficient rats with increased IOP. Interestingly, complement depletion also resulted in reduction of calcium influx and levels of BAD in the retinal cells of the eyes with increased IOP. Together, our results provide evidence that complement mediated apoptosis plays a pivotal role in the loss of RGCs in chronic ocular hypertension model of glaucoma.

Preclinical Retinal Neurodegeneration in a Model of Multiple Sclerosis

“…In both cases, macrophage recruitment into the retina and BRB disturbances occur (Bhattacherjee et al, 1983;McMenamin and Crewe, 1995;Golubnitschaja et al, 2002;Grieshaber and Flammer, 2007), accompanied by degeneration of RGCs (Quigley, 1999;El-Remessy et al, 2008). In addition, glaucoma-linked activation of the complement cascade has also been shown to induce both synaptic loss and apoptosis (Stevens et al, 2007;Jha et al, 2011).…”

The Complex Role of Neuroinflammation in Glaucoma

“…Significant deposition of MAC was found in glaucomatous RGCs in human eyes and in experimental models of glaucoma (Kuehn et al 2006;Jha et al 2011;Howell et al 2013). Drug inhibition of complement activation reduced MAC deposition and apoptosis of RGCs in a rat model of glaucoma (Jha et al 2011). Furthermore, C5-deficient DBA/2J mice showed reduced neurodegeneration compared with C5-sufficient DBA/2J mice (Howell et al 2013 Figure 5.…”

Intravitreal injection of β-crystallin B2 improves retinal ganglion cell survival in an experimental animal model of glaucoma

“…Especially several experimental studies indicated a neuroprotective potential of β-crystallin B2 when it comes to neuronal impairment in vivo and in vitro [30–32]. Concerning the crystallin function, a conclusive mode of action could not be revealed yet [26, 33, 34]. Thus, crystallins might function as critical modulators in the course of glaucoma and might be integral to glaucomatous neurodegeneration.…”