Exploring The Effects Of Rapamycin Eye Drops On Reducing Intraocular Pressure And Protecting Retinal Ganglion Cells

Purpose: The mammalian target of rapamycin(m TOR)is a serine/threonine protein kinase that not only participates in cell growth and survival,but also regulates the actin cytoskeleton by mediating the activity of small GTPase proteins.The purpose of this study was to investigate whether rapamycin,an inhibitor of the m TOR signaling pathway,can lower intraocular pressure(IOP)by regulating the trabecular meshwork structure and whether it can improve the survival rate of retinal ganglion cells(RGCs)by inhibiting glia cell activation.Methods: Ocular hypertension was unilaterally induced in adult Sprague-Dawl ey rats by anterior chamber injection of microbeads,and the other eyes was injected with an equal amount of sterile saline as control groups.After the IOP was elevated,the eyes were continuously topically administration with rapamycin or a solvent for 2weeks,and IOP was monitored during this period.The aqueous humor of rats was measured by high-performance liquid chromatography(HPLC)to assess the concentr ation of rapamycin.In vitro,human trabecular meshwork(TM)cells were treated with rapamycin at different times,and changes in F-actin distribution,m TOR protein phosphorylation,and Rho A protein activation in TM cells were studied by cell biology techniques.Histopathological changes in the retina were assessed by hematoxylin and eosin staining.RGCs degeneration and gliosis were assessed by immunostaining and Western blotting.Results: In this study,topical administration of rapamycin reduced the IOP in rats compared to that in the vehicle control group,and rapamycin was detected in rat aqueous humor.In vitro,TM cells were exposed to rapamycin,which caused disruption of actin bundles and significantly inhibited the m TOR phosphorylation and Rho A protein activation.In vivo,the rapamycin treatment significantly reduced the retinal damage and RGCs loss and attenuated reactive glial cells and the release of proinflammatory mediators following elevated IOP.Conclusions: Rapamycin may regulate the cytoskeleton of TM by mediating the activity of Rho A,and promote the outflow of aqueous humor,which lower IOP.In addition,rapamycin can attenuate the damage of RGCs induced by glial-associated proinflammatory factors.Therefore,these results demonstrate that rapamycin can not only lower IOP,but also improve the survival rate of RGCs in animal models of chronic ocular hypertension.