Rapamycin Is Neuroprotective in a Rat Chronic Hypertensive Glaucoma Model

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.

New strategies for neuroprotection in glaucoma, a disease that affects the central nervous system

“…Under this experimental condition treatment with the autophagy inducer rapamycin exerted protective effects, while autophagy inhibition exacerbated axonal damage (Kitaoka et al, 2013). Vice versa, in the same glaucoma model induced by laser photocoagulation, Su et al (2014) reported a significant reduction of RGC loss following treatment with rapamycin.…”

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

“…Although autophagy and apoptosis can coexist in the same damaged RGC, they do not necessarily overlap and can occur independently [58,92]. Autophagy can occur before neuronal apoptosis in aluminum-insulted astrocytes, a chronic hypertensive glaucoma model, and an optic nerve axotomy mouse model [46,93,94]. Similarly, in a chronic glaucoma model, autophagy activation occurs earlier than RGC loss [58].…”

P7C3 Suppresses Neuroinflammation and Protects Retinal Ganglion Cells of Rats from Optic Nerve Crush

“…This interaction may be due to a relief of negative feedback loop from the mTOR signaling pathway. 26 Akt is closely associated with cellular survival, 42 and the levels of phosphorylated Akt are decreased in the eyes with experimental glaucoma 43 and after excitotoxicity in RGCs. 44 Thus, enhanced phosphorylation of Akt in the retina may have beneficial effects on the RGCs.…”