Combined inhibition of apoptosis and necrosis promotes transient neuroprotection of retinal ganglion cells and partial axon regeneration after optic nerve damage

Kayama, M.; Omura, K.; Murakami, Y.; Reshef, E.; Thanos, A.; Morizane, Y.; Gianni, A.; Nakazawa, T.; Miller, J.; Benowitz, L.; Vavvas, D.

doi:10.1101/357566

bioRxiv · 10.1101/357566

Combined inhibition of apoptosis and necrosis promotes transient neuroprotection of retinal ganglion cells and partial axon regeneration after optic nerve damage

Kayama, M.·Omura, K.·Murakami, Y.·Reshef, E.·Thanos, A.·Morizane, Y.·Gianni, A.·Nakazawa, T.·Miller, J.·Benowitz, L.·Vavvas, D.

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Abstract

Retinal ganglion cell (RGC) death is the hallmark of glaucoma. Axonal injury is thought to precede RGC loss in glaucoma, and thus studies using an optic nerve (ON) crush model have been widely used to investigate mechanisms of cell death that are common to both conditions. Prior work has focused on the involvement of caspases in RGC death, but little is known about the contribution of other forms of cell death such as necrosis. In this study we show that receptor interacting protein (RIP) kinase-mediated necrosis normally plays a role in RGC death and acts in concert with caspase-dependent apoptosis. The expression of RIP3, a key activator of RIP1 kinase, as well as caspase activity, increased following ON injury. Caspase inhibition alone failed to provide substantial protection to injured RGCs and unexpectedly exacerbated necrosis. In contrast, pharmacologic or genetic inhibition of RIP kinases in combination with caspase blockade delayed both apoptotic and necrotic RGC death, although RGCs still continued to die. Furthermore, inhibition of RIP1 kinase promoted a moderate level of axon regeneration that was only minimal affected by caspase inhibition. In conclusion, multiple approaches are required for effective RGC death prevention and axonal regeneration. Further studies are needed to elucidate more effective long term strategies that can lead to sustained neuroprotection and regeneration.

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Kayama, M., Omura, K., Murakami, Y., Reshef, E., Thanos, A., Morizane, Y., Gianni, A., Nakazawa, T., Miller, J., Benowitz, L., Vavvas, D.. 2018-06-27. Combined inhibition of apoptosis and necrosis promotes transient neuroprotection of retinal ganglion cells and partial axon regeneration after optic nerve damage. https://doi.org/10.1101/357566

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