FTY720 Protects Retinal Ganglion Cells in Experimental Glaucoma

PURPOSE. To investigate the neuroprotective effects of sphingosine-1-phosphate (S1P) analogue fingolimod (FTY720) in experimental glaucoma in rats. METHODS. A unilateral chronic ocular hypertensive model was established by injections of microbeads into the anterior eye chamber of adult Sprague-Dawley rats. Fingolimod was administered to one group of rats intraperitoneally every week for 3 months. The scotopic threshold response (STR) was recorded to assess the function of the inner retina. Changes in cell density in the ganglion cell layer (GCL) were evaluated by hematoxylin and eosin staining on retinal sections and axonal count of the optic nerve was performed using Bielschowsky's silver staining. Effects of drug treatment on activation of Akt and Erk1/2 were evaluated using Western blotting by assessing phosphorylation levels of these proteins. The expression of S1P receptors in the optic nerve head region was also evaluated using Western blotting and immunohistochemistry. RESULTS. Administration of FTY720 reduced the loss of STR amplitude in glaucomatous eyes (P < 0.05). Counting and plotting the cell numbers/axonal density showed significant neural preservation in the GCL and the optic nerve (P < 0.05). An increased phosphorylation level of Akt and Erk1/2 following FTY720 administration was observed. Both S1P1 and S1P5 receptors were found to be expressed in the retina and the expression of S1P1R was upregulated in experimentally-induced glaucoma. CONCLUSIONS. This study demonstrates, for the first time, that FTY720 could act as a neuroprotective agent to protect retinal ganglion cells in experimental glaucoma. Administration of this drug significantly reduces the structural and functional loss of the inner retina elicited indicating that it may potentially be used to attenuate neuronal loss and optic nerve damage in glaucomatous patients.