Abstract
Purpose :
Nonarteritic anterior ischemic optic neuropathy(NAION) is the most common cause of sudden optic nerve-related vision loss, currently without effective treatment. Trabodenoson is a selective adenosine A1 receptor(A1R) agonist, recently evaluated as an ocular antihypertensive treatment in a clinical trial. A1R agonists have been shown to have neuroprotective properties. We previously reported that Trabodenoson improves RGC survival in the rodent NAION model(rNAION). Here we report Trabodenoson's site of action and neuroprotective mechanisms.
Methods :
Male Sprague Dawley rats received 3% trabodenoson or placebo drops twice daily to both eyes starting 3 days prior to induction. rNAION induction was generated as previously described. Eye drops continued for 2 days post induction in short-term study and for 21 days in long-term study. Optic nerve(ON) and retinae were examined via slit lamp and SD-OCT at 2 days post induction. Short-term study animals were euthanized immediately after OCT examination, retinae, optic nerve head(ONH) and the posterior ON were collected for gene expression study(rq-PCR)of variety of genes and for immunohistochemical analyses. Long-term study animals were euthanized 30 days post induction. Whole mount RGC stereology and optic nerve immunohistochemistry performed.
Results :
Topical Trabodenoson reduced ONH edema in the rNAION model compared with placebo treated eyes by SD-OCT. Immunohistochemically, retinal A1R expression was strongest in the RGC layer. A1R was expressed in the ONH, and co-localized with the astrocyte markers GFAP and Aldh1L1, and with the vascular basement membrane marker, laminin. By rq-PCR, rNAION-induced, Trabodenoson treated animals revealed increased levels of retinal Thy-1 and Mmp-2, HO-1 and nestin expression in the ONH, while no difference was seen in posterior ON segments in any group. Long term study revealed that it improved RGC survival and axon SMI preservation.
Conclusions :
Trabodenoson reduced rNAION associated ONH edema, and preserved retinal Thy-1 expression, likely associated with the increased long-term RGC survival. It increased ONH expression of genes associated with astrocyte-related neuroprotective mechanisms. This suggests that Trabodenoson exert direct neuro-protective effects distinct from its antihypertensive effects, targeted to the ONH, may be an appropriate adjunctive therapeutic for optic nerve diseases such as NAION and open angle glaucoma.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.