Similarities and differences between primary and secondary degeneration of the optic nerve and the effect of minocycline

Purpose: To investigate the mechanism of secondary degeneration of the optic nerve, and to evaluate the neuroprotective effect of minocycline in this process. Methods: A partial transection model that morphologically separates primary and secondary degeneration was applied unilaterally in 152 Wistar rat eyes. The involvement of pro-apoptotic, pro-survival and inflammatory pathways was analyzed by quantitative real-time PCR and immunohistochemistry at multiple time points. The neuroprotective effect of daily intraperitoneal injections of minocycline 22 mg/kg/day was evaluated at 7, 11 and 21 days post-injury. Retrograde labeling of retinal ganglion cells (RGCs) with fluorogold was via the superior colliculus, and surviving RGCs were counted using retinal whole mounts. Results: Both primary and secondary degeneration led to a significant up-regulation of the pro-apoptotic genes, GADD45α, ei24 and CDK2, and the pro-survival gene, IAP-1. These processes differed, however, in their reaction to minocycline. Minocycline protected RGC death from secondary degeneration at 11 days (6±8% loss compared to 37±7% in the saline-treated group, n=15, P=0.012), and at 21 days (42±7% versus 64±7% respectively, n=15, P=0.06) after partial transection. In contrast, its effect on primary degeneration was not significant. Conclusions: While the genetic profile supported similarities between primary and secondary degeneration of the optic nerve, the specific effect of minocycline on secondary degeneration revealed a potential difference between the two. The mechanism underlying secondary degeneration, and its role in optic neuropathies such as glaucoma, awaits further studies.