Rapamycin is neuroprotective in a rat chronic hypertensive glaucoma model

• Published in: PloS one Vol. 9; no. 6; p. e99719
• Main Authors: Su, Wenru, Li, Zuohong, Jia, Yu, Zhuo, Yehong
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.06.2014; Public Library of Science (PLoS)
• Subjects: AKT protein; Alzheimer's disease; Alzheimers disease; Animals; Apoptosis; Autophagy; Blindness; Cell death; Cell survival; Cell Survival - drug effects; Cells, Cultured; Chronic Disease; Disabled people; Disease Models, Animal; Female; Glaucoma; Glaucoma - pathology; Glaucoma - physiopathology; Hypertension; Kinases; Labeling; Laboratories; Medicine and Health Sciences; Neuroprotection; Neuroprotective Agents - pharmacology; Neurotoxicity; NF-κB protein; Ocular Hypertension - pathology; Ocular Hypertension - physiopathology; Optic nerve; People with disabilities; Phosphorylation; Rapamycin; Rats; Rats, Sprague-Dawley; Retina; Retinal ganglion cells; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - pathology; Retinal Ganglion Cells - physiology; Rodents; Signaling; Sirolimus - pharmacology; Surgery; Survival; Tumor necrosis factor; Tumor necrosis factor-α; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0099719

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.