Axonal protection by short-term hyperglycemia with involvement of autophagy in TNF-induced optic nerve degeneration.

Kana Sase,Yasushi Kitaoka,Yasunari Munemasa,Kaori Kojima,Hitoshi Takagi

doi:10.3389/fncel.2015.00425

Kana Sase, Yasushi Kitaoka + Show 3 more

Open Access

https://doi.org/10.3389/fncel.2015.00425

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Abstract

Previous reports showed that short-term hyperglycemia protects optic nerve axons in a rat experimental hypertensive glaucoma model. In this study, we investigated whether short-term hyperglycemia prevents tumor necrosis factor (TNF)-induced optic nerve degeneration in rats and examined the role of autophagy in this axon change process. In phosphate-buffered saline (PBS)-treated rat eyes, no significant difference in axon number between the normoglycemic (NG) and streptozotocin (STZ)-induced hyperglycemic (HG) groups was seen at 2 weeks. Substantial degenerative changes in the axons were noted 2 weeks after intravitreal injection of TNF in the NG group. However, the HG group showed significant protective effects on axons against TNF-induced optic nerve degeneration compared with the NG group. This protective effect was significantly inhibited by 3-methyladenine (3-MA), an autophagy inhibitor. Immunoblot analysis showed that the LC3-II level in the optic nerve was increased in the HG group compared with the NG group. Increased p62 protein levels in the optic nerve after TNF injection was observed in the NG group, and this increase was inhibited in the HG group. Electron microscopy showed that autophagosomes were increased in optic nerve axons in the HG group. Immunohistochemical study showed that LC3 was colocalized with nerve fibers in the retina and optic nerve in both the NG and HG groups. Short-term hyperglycemia protects axons against TNF-induced optic nerve degeneration. This axonal-protective effect may be associated with autophagy machinery.

Highlights

Glaucoma is a cause of visual field defect due to loss of nerve fibers and thinning of the neuronal rim of the optic nerve head
We have recently demonstrated that the activation of autophagy leads to axonal protection in the hypertensive experimental glaucoma model (Kitaoka et al, 2013) and in the tumor necrosis factor (TNF)induced optic nerve degeneration model (Kojima et al, 2014)
Effects of Hyperglycemia and 3-MA on TNF-Induced Axonal Degeneration In phosphate-buffered saline (PBS)-injected eyes, there was no significant difference in axon number between the HG and NG groups (Figures 1A,C,F)

Summary

INTRODUCTION

Glaucoma is a cause of visual field defect due to loss of nerve fibers and thinning of the neuronal rim of the optic nerve head. Autophagy and high glucose in the optic nerve are risk factors for primary open-angle glaucoma (POAG; Leske et al, 1994, 2008; Sommer and Tielsch, 1996; Coleman and Miglior, 2008; Francis et al, 2008; Topouzis et al, 2011). Short-term hyperglycemia attenuated axonal degeneration and retinal ganglion cell (RGC) death after experimentally induced ocular hypertension (Ebneter et al, 2011). We have recently demonstrated that the activation of autophagy leads to axonal protection in the hypertensive experimental glaucoma model (Kitaoka et al, 2013) and in the tumor necrosis factor (TNF)induced optic nerve degeneration model (Kojima et al, 2014). In the present study, we investigated whether short-term hyperglycemia prevents TNF-induced optic nerve degeneration and examined the role of autophagy in this axon change process

MATERIALS AND METHODS

RESULTS

DISCUSSION