Regulation of cell death and survival pathways in secondary degeneration of the optic nerve a long-term study

Purpose: To investigate cell death and survival pathways in secondary degeneration of the optic nerve (ON) and retina over a period of 6 months. Methods: A partial transection model of the ON that morphologically separates primary and secondary degeneration was applied unilaterally in 89 Wistar rat eyes. The upper third of the retinas were analyzed for primary degeneration, while the lower third of the retinas were analyzed for secondary degeneration. The involvement of members of the mitogen-activated protein (MAP) kinase pathway and the PI-3-kinase/Akt pathway were evaluated in primary and secondary degeneration in multiple time points over a period of 6 months using immunohistochemistry and western blotting. Results were compared to corresponding areas from control fellow eyes. Results: All investigated members of the MAP kinase pathway were significantly activated in primary degeneration, secondary degeneration or both. P-SAPK/JNK and P-ERK were activated in primary degeneration without a concomitant activation in secondary degeneration. The prosurvival protein p-Akt, a member of the PI-3-kinase survival pathway, was significantly activated in secondary but not in primary degeneration. P-c-jun and p-ATF were significantly activated in both primary and secondary degeneration. The time-dependent pattern of activation was different for each protein and in secondary degeneration the activation of these proteins was usually short termed. Conclusions: The significant involvement of the MAP kinase pathway and the PI-3-kinase survival pathway in secondary degeneration of the ON and retina is short termed despite continuous retinal ganglion cells (RGCs)apoptosis for at least 6 months.