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J. W. Lewcock, M. Chen, A. Ghosh, J. Maloney, C. Pozniak, M. Miller, R. Watts; Identification of New Neuroprotective Strategies for the Treatment of Glaucoma Through Screening Inhibitors of Axon Degeneration in vitro. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6096.
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Glaucoma results in vision loss and eventual blindness that is caused by selective degeneration of retinal ganglion cells (RGCs). An unmet need exists for therapeutics with potential to rescue RGCs independent of IOP. Recent studies in animal models suggest that initial insult is to RGC axons at the lamina cribosa, and that degeneration of RGC axons significantly precedes neuronal apoptosis. Axon degeneration is poorly understood, and defining specific pathways that drive this process may lead to new neuroprotective targets for the treatment of glaucoma.
An in vitro screen was performed, in which small molecules with known targets were tested for their ability to inhibit axon degeneration. For pathways of particular interest, neurons were transfected with siRNA or dominant negative constructs to validate hits from the screen. The role of each of the pathways identified in glaucoma was then investigated through examination of retinas from mouse and rat models of disease.
Several well known pathways were found to play a role in axon degeneration. Small molecule inhibitors of JNK, P38α, and EGFR all significantly delayed the degeneration of axons independent of apoptosis. The protection observed through inhibition of each pathway had a unique profile in terms of spatial and temporal requirements. Additional experiments investigating the JNK pathway demonstrated that axon degeneration was largely based on the JNK2 /JNK3 stress response pathway. JNKs were also activated in RGCs during the course of degeneration in animal models of glaucoma.
JNK, P38α, and EGFR were identified as 3 pathways previously not known to play a role in the process of axon degeneration independent of apoptosis. The JNK pathway is of particular interest, as JNK2/3 have a well known role in neuronal apoptosis in addition to their role in axon degeneration shown here. Thus, targeting this pathway therapeutically may prove to be an effective strategy to directly inhibit the degeneration of RGCs in glaucoma patients.
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