Topical Trabodenoson Is Neuroprotective in a Rodent Model of Anterior Ischemic Optic Neuropathy (rNAION)

Abstract

PurposeNonarteritic anterior ischemic optic neuropathy (NAION) is the leading cause of sudden optic nerve–related vision loss currently without effective treatment. We evaluated the neuroprotective potential of ocular (topical) delivery of trabodenoson, a selective A1 receptor mimetic, in a rodent model of NAION (rNAION).MethodsDaily topical delivery of 3% trabodenoson or vehicle administered in both eyes 3 days prior to rNAION induction and for 21 days post induction. Retinal appearance and optic nerve head (ONH) edema was evaluated using spectral-domain optical coherence tomography (SD-OCT). Retinal function was evaluated before and after induction by ganzfeld electroretinography (ERG). Brn3a(+) retinal ganglion cells (RGCs) were quantified by stereology. Axonal ultrastructure was evaluated by electron microscopy.ResultsTrabodenoson-treated eyes had significantly reduced optic nerve (ON) edema compared with vehicle-treated eyes (ANOVA, P < 0.05). Electrophysiologically, there was a nonsignificant trend toward b-wave and oscillatory potential (OP) preservation in the trabodenoson-treated eyes. RGC counts were higher in trabodenoson-treated eyes compared to vehicle (74% versus 47% of the contralateral eye; two-tailed t-test; P = 0.01), as were ON axons. No overt morphologic differences in cell inflammation were observed between vehicle- and trabodenoson-treated ONHs, but trabodenoson-treated ONHs revealed increased expression of astrocyte-related neuroprotective responses.ConclusionsTrabodenoson preserves RGCs in the rodent NAION model. While previous clinical trials focused on trabodenoson's ocular antihypertensive effect, our data suggest trabodenoson's primary target may be both the retina and ONH. Selective adenosine A1 agonists may prove an appropriate neuroprotective adjunctive for ischemia-related ON diseases such as NAION and glaucoma.Translational RelevanceRGC and ON neuroprotection in ischemic neuropathies may be achievable by topical administration of A1 adenosine agonists rather than by simply relying on intraocular pressure reduction.

Neuroprotection and Neuroregeneration Strategies Using the rNAION Model: Theory, Histology, Problems, Results and Analytical Approaches

“…Although Trabodenoson only moderately suppressed ONH edema (564 ± 14.52 um sem for vehicle vs. 512.15 ±20.12 um sem for Trabodenoson; n = 13), the difference was significant (two-tailed t -test: p = 0.05). Even more importantly, however, Trabodenoson was potently RGC neuroprotective, with RGC loss reduced from 53.2 ± 7.1% sem in vehicle-treated animals to 27.9 ± 6.5% sem RGC loss in animals treated with Trabodenoson ( Figure 7 B; data derived from [ 45 ]). These results also were statistically significant (two-tailed t -test; p = 0.01) and suggest that adenosine receptor agonism is potently neuroprotective, with effects only partly exerted through edema reduction.…”

Non-Arteritic Anterior Ischemic Optic Neuropathy: Challenges for the Future

“…Potentially synergistic combination therapies with PGJ 2 are being explored, though up to this point, none have demonstrated efficacy beyond that of PGJ 2 alone ( 39 ). Daily topical ocular delivery of trabodenoson, a selective adenosine A 1 agonist, was shown to reduce ON edema and preserve RGCs in rNAION, when compared with vehicle ( 40 ). Further, intravitreal injection of ciliary neurotrophic factor (CNTF) was shown to promote RGC survival when administered one day after rNAION induction ( 41 ).…”

Anti-NOGO Antibody Neuroprotection in a Rat Model of NAION

“…We previously have had success in preventing loss of visual function and retinal ganglion cells (RGC) in our rat model of NAION (rNAION), using intravitreal and systemically administered prostaglandin 15-deoxy 12,14 delta prostaglandin J2 (PGJ 2 ) as well as using topical administration of trabodenoson. 9 However, although delayed administration of these agents has successfully prevented damage in rNAION and pNAION (neuroprotection), it does not restore either optic nerve function or optic nerve integrity (neuroregeneration). 10 We wished to evaluate a neuroregenerative approach in NAION treatment.…”