Abstract
Glaucoma is characterized by a progressive damage of the retina and the optic nerve. Despite a huge research interest, the exact pathomechanisms are still unknown. In the experimental autoimmune glaucoma model, rats develop glaucoma-like damage of the retina and the optic nerve after immunization with an optic nerve antigen homogenate (ONA). An early activation of the complement system, even before optic nerve degeneration, was reported in this model. Here, we investigated the effects of a monoclonal antibody against complement factor C5 on optic nerves. Rats were immunized with ONA and compared to controls. In one eye of some ONA animals, the antibody against C5 was intravitreally injected (15 μmol: ONA + C5-I or 25 μmol: ONA + C5-II) before immunization and then every 2 weeks. After 6 weeks, optic nerves were processed for histology (n = 6/group). These analyses demonstrated that the intravitreal therapy reduced the depositions of the membrane attack complex compared to ONA animals (ONA + C5-I: p = 0.005; ONA + C5-II: p = 0.002). Cellular infiltration was significantly reduced in the ONA + C5-I group (p = 0.003), but not in ONA + C5-II tissues (p = 0.41). Furthermore, SMI-32 staining revealed that neurofilament was preserved in both treatment groups compared to ONA optic nerves (both p = 0.002). A decreased amount of microglia was found in treated animals in comparison to the ONA group (ONA + C5-I: p = 0.03; ONA + C5-II: p = 0.009). We observed, for the first time, that a complement system inhibition could prevent optic nerve damage in an autoimmune glaucoma model. Therefore, complement inhibition could serve as a new therapeutic tool for glaucoma.
Highlights
Glaucoma is one of the leading causes of blindness worldwide (Flaxman et al 2017; Tham et al 2014)
Regarding the optic nerve antigen homogenate (ONA) group, the amount of C3+ cells was not significantly different from controls (p = 0.10; Fig. 2 (a–a′′′), (b–b′′′), and (e); Table 2). In both intravitreally treated groups, significantly more C3+ cells were found compared to controls (ONA + C5-I: p = 0.002; ONA + C5-II: p = 0.04)
0.012 ± 0.0 0.015 ± 0.0 0.84 0.012 ± 0.0 0.99 0.82 0.017 ± 0.0 0.65 0.97 treatment groups (ONA + C5-I: p = 0.005; ONA + C5-II: p = 0.002; Fig. 2 (c–c′′′), (d–d′′′), and (f); Table 2). Between both therapy groups and controls no significant differences in membrane attack complex (MAC)+ cells were detected (ONA + C5-I: p = 0.95; ONA + C5-II: p = 0.53). These results suggest a successful inhibition of the terminal complement pathway in the optic nerve via intravitreal C5 therapy, similar to recent findings in the retina (Reinehr et al 2019a)
Summary
Glaucoma is one of the leading causes of blindness worldwide (Flaxman et al 2017; Tham et al 2014). Major parts of the pathogenesis of this neurodegenerative disease are still unknown. The currently available therapies, comprising local medication and surgical methods, are often unsatisfactory and have considerable side effects (Gupta and Chen 2016). Glaucoma, especially NTG, still represents a challenge for the clinician ophthalmologist, making further research in this field necessary.
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