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Stephanie C Joachim, Sabrina Reinehr, Gesa Stute, Christoph Ullmer, H Burkhard Dick; Autotaxin protects retinal ganglion cells in an autoimmune glaucoma model. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6144.
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The autotaxin-lysophosphatidic acid (ATX-LPA) signaling pathway plays a role in a variety of autoimmune diseases, such as rheumatoid arthritis, or neurodegeneration. A link to a role in the pathogenesis of glaucoma is suggested by an overactive ATX/LPA axis in patient’s aqueous humor samples. Hence, it was tested if ATX inhibition protects retinal ganglion cells (RGC) and optic nerve axons in an autoimmune glaucoma model using two different ATX inhibitors. In this model, RGC loss and optic nerve degeneration occur IOP independently.
Rats were immunized with bovine optic nerve homogenate antigen (ONA). Following groups were compared: control group (Co), immunization group (ONA) and the ONA plus autotaxin inhibitors, PF-8380 (60 mpk; Roche) and ATX-R (20 mpk; Roche), groups. Oral treatment was started 7 days prior to immunization. 28 days after immunization optic nerves and retinas were processed for immunohistology to evaluate neurofilament (SMI-32), RGCs (Brn-3a), macroglia (GFAP), and microglia (Iba1, ED1).
Significantly fewer RGCs were observed in the ONA (47.3±3.2 cells/mm) group when compared to controls (63.2±11.4 cells/mm; p=0.039). No significant RGC loss was noted in the PF-8380 (51.7±9.7 cells/mm; p=0.21) and ATX-R group (48.3±9.6 cells/mm; p=0.06). Gliosis was seen in ONA retinas (p=0.027), but not in the treatment groups (both: p=0.99). In the ONA group, significantly more microglia (22.1±7.8 cells/mm; p=0.042) as well as active microglia (7.7±6.3 cells/mm; p=0.021) were observed in comparison to controls (Iba1: 13.7±3.0 cells/mm; ED1: 1.5±1.3 cells/mm). Whereas no changes were noted in the PF-8380 (Iba1: 18.0±4.8 cells/mm; ED1: 2.5±1.7 cells/mm) and ATX-R (Iba1: 19.8±2.8 cells/mm; ED1: 5.1±1.9 cells/mm) treatment group. A significantly increased SMI-32 score was seen in the ONA group (p=0.025), indicating degenerated neurofilaments, but not in the treatment groups (p>0.7). Additionally, treatment with PF-8380 and ATX-R decreased the number of microglia in the optic nerve.
The two different ATX inhibitors protected RGCs and optic nerve axons in the autoimmune glaucoma model. Results from this study indicate that ATX inhibitors might serve as novel therapeutic targets for glaucoma.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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