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Abstract
Spermidine acts as an endogenous free radical scavenger and inhibits the action of reactive oxygen species. In this study, we examined the effects of spermidine on retinal ganglion cell (RGC) death in a mouse model of optic nerve injury (ONI). Daily ingestion of spermidine reduced RGC death following ONI and sequential in vivo retinal imaging revealed that spermidine effectively prevented retinal degeneration. Apoptosis signal-regulating kinase-1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase kinase kinase and has an important role in ONI-induced RGC apoptosis. We demonstrated that spermidine suppresses ONI-induced activation of the ASK1-p38 mitogen-activated protein kinase pathway. Moreover, production of chemokines important for microglia recruitment was decreased with spermidine treatment and, consequently, accumulation of retinal microglia is reduced. In addition, the ONI-induced expression of inducible nitric oxide synthase in the retina was inhibited with spermidine treatment, particularly in microglia. Furthermore, daily spermidine intake enhanced optic nerve regeneration in vivo. Our findings indicate that spermidine stimulates neuroprotection as well as neuroregeneration, and may be useful for treatment of various neurodegenerative diseases including glaucoma.
Highlights
Glaucoma is one of the leading causes of vision loss in the world and it is estimated that this condition will affect more than 80 million individuals worldwide by 2020, with at least 6–8 million individuals becoming bilaterally blind.[8]
We previously reported that loss of glutamate transporters (EAAC1 or GLAST) in mice leads to retinal ganglion cells (RGCs) degeneration that is similar to NTG13 and these animal models have been useful in examining potential therapeutic targets.[14,15,16]
As the inducible nitric oxide synthase (NOS) expression level is upregulated in activated microglia, which can cause RGC death,[26,27] we examined whether spermidine modulates the level of microglial iNOS expression following optic nerve injury (ONI)
Summary
Glaucoma is one of the leading causes of vision loss in the world and it is estimated that this condition will affect more than 80 million individuals worldwide by 2020, with at least 6–8 million individuals becoming bilaterally blind.[8] Glaucoma is characterized by progressive degeneration of RGCs and their axons, which are usually associated with elevated intraocular pressure, but there is a subset of glaucoma termed normal tension glaucoma (NTG) that presents with statistically normal intraocular pressure. There are several animal models of glaucoma, including DBA/2J mice,[9] and inducible models such as cauterization of episcleral veins.[10,11,12] In addition, we previously reported that loss of glutamate transporters (EAAC1 or GLAST) in mice leads to RGC degeneration that is similar to NTG13 and these animal models have been useful in examining potential therapeutic targets.[14,15,16].
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