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

To investigate the mechanism of secondary degeneration of the optic nerve, and to evaluate the neuroprotective effect of minocycline in this process. 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. Both primary and secondary degeneration led to a significant up-regulation of the pro-apoptotic genes, GADD45 alpha, 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. 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.