Rapamycin Is Neuroprotective in a Rat Chronic Hypertensive Glaucoma Model

Wenru Su,Yu Jia,Yehong Zhuo,Zuohong Li,Andreas Ohlmann

doi:10.1371/journal.pone.0099719

Abstract

Glaucoma is a leading cause of irreversible blindness. Injury of retinal ganglion cells (RGCs) accounts for visual impairment of glaucoma. Here, we report rapamycin protects RGCs from death in experimental glaucoma model and the underlying mechanisms. Our results showed that treatment with rapamycin dramatically promote RGCs survival in a rat chronic ocular hypertension model. This protective action appears to be attributable to inhibition of neurotoxic mediators release and/or direct suppression of RGC apoptosis. In support of this mechanism, in vitro, rapamycin significantly inhibits the production of NO, TNF-α in BV2 microglials by modulating NF-κB signaling. In experimental animals, treatment with rapamycin also dramatically inhibited the activation of microglials. In primary RGCs, rapamycin was capable of direct suppression the apoptosis of primary RGCs induced by glutamate. Mechanistically, rapamycin-mediated suppression of RGCs apoptosis is by sparing phosphorylation of Akt at a site critical for maintenance of its survival-promoting activity in cell and animal model. These results demonstrate that rapamycin is neuroprotective in experimental glaucoma, possibly via decreasing neurotoxic releasing and suppressing directly apoptosis of RGCs.

Highlights

IntroductionA common feature of glaucoma is elevated intraocular pressure (IOP) that results in the progressive loss of retinal ganglion cells (RGCs)
Glaucoma is a leading cause of severe irreversible visual impairment and blindness
The Neuroprotective Effects of Rapamycin in the COH To evaluate the role of rapamycin in glaucoma neuroprotection, we adapted a rat chronic ocular hypertension model that is a wellestablished animal model of human glaucoma

Summary

Introduction

A common feature of glaucoma is elevated intraocular pressure (IOP) that results in the progressive loss of retinal ganglion cells (RGCs). The development of new strategies that prevent RGC death and slow disease progression has become the primary goal of glaucoma therapy [1,2]. The underlying mechanism of rapamycin-mediated neuroprotection remains elusive. The role rapamycin plays in glaucoma is unclear. In this study we explored the role of rapamycin in neuroprotection in experimental glaucoma and the potential cellular and molecular mechanisms. We found that rapamycin can protect RGCs from death in a rat chronic ocular hypertension model (COH) of glaucoma. To the best of our knowledge, these findings provide the compelling evidence that rapamycin is neuroprotective in experimental glaucoma

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Conclusion