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H. Levkovitch-Verbin, Y. Nisgav, R. Dardik, S. Vander, S. Melamed; Axonal Degeneration in Glaucoma Has Different Molecular Components Than Retinal Ganglion Cell Apoptosis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3661.
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It was recently suggested that axonal degeneration pathways in glaucoma may have different molecular components than those in retinal ganglion cell (RGC) apoptosis. Distinct degeneration pathways were activated in various parts of the RGC of DBA/2J mice that developed glaucoma. In this study, we compared changes in molecular pathways between optic nerve (axonal) degeneration and RGC body apoptosis using 2 models of optic nerve and retinal damage: experimental glaucoma and N-Methyl-D-Aspartate (NMDA) toxicity.
Experimental glaucoma was induced in 60 rats using the translimbal photocoagulation laser model. The rats were sacrificed on days 1, 4, 8, 14, and 30. Retinal toxicity was induced by intravitreal injections of NMDA in other rats (n=48) that were sacrificed at 12 hours and days 1, 3, and 6. The optic nerves were removed by a transcranial approach, and the retinas were excised and immediately frozen for reverse transcriptase-polymerase chain reaction. The expression of BAX, BAD, Bcl-2, Bclxl (bcl-2 family), Gadd45α (p53 pathway) and the anti-apoptotic gene (caspase inhibitor) IAP1 were investigated separately in the optic nerves and retinas.
Significant up-regulation of BAX at day 14 (p<0.05) and significant down-regulation of Bcl-2 at days 8 and 14 (p<0.05) were detected in the optic nerves and retinas in the experimental glaucoma model. The proapoptotic gene Gadd45α was significantly up-regulated from days 4-14 in the optic nerves (p<0.05) and from days 4-30 in the retinas (p<0.01). Interestingly, IAP1 was significantly up-regulated in the RGC bodies from days 8-30 (p≤0.01), but unchanged or down-regulated in the optic nerves (p=0.07 for day 4). The NMDA injections model revealed significant up-regulation of the proapoptotic genes BAX, BAD (bcl-2 family) and Gadd45α from 12 hours until 3 days in the optic nerves and retinas(p<0.05), returning to baseline at 6 days. The pro-survival caspase inhibitor gene IAP1 was significantly up-regulated beginning only 3 days after NMDA injections in the optic nerves and retinas(p≤ 0.05), but the pro-survival genes Bcl-2 and Bclxl were not affected by NMDA injections at any time point either in the nerves or the retinas
Degeneration pathways in experimental glaucoma and NMDA toxicity model may be different. Similar proapoptotic pathways are activated in the RGC body and axon in experimental glaucoma but the activation of pro-survival pathways is significantly different. In contrast, molecular changes in axonal degeneration and RGC bodies are similar in the NMDA retinal toxicity model.
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