MIF Inhibitor Ibudilast Prevents Retinal Cell Death in Chick Excitotoxic Retinal Damage Model

Abstract

Purpose : Ibudilast, a clinically-relevant macrophage migration inhibitory factor (MIF) inhibitor, is in clinical trials for a number of neurologic and other conditions. Excitotoxic retinal damage occurs in a number of conditions, such as glaucoma, diabetic retinopathy, and blast injury. We hypothesized that ibudilast would exhibit retinal neuroprotection in a chick N-methyl-D-aspartate (NMDA) excitotoxic damage model.

Methods : The protocol was approved by the IACUC. Toxicity of the maximal soluble dose of intraocular ibudilast was tested in undamaged leghorn chicks (20uL of ibudilast 4.5mg/mL, left eye and vehicle (sterile water), fellow eye). TUNEL was used to evaluate cell death at day 1 (n=5). Retinal thickness measurements were obtained with immunohistochemistry at 1 day (n=5) or 21 days (n=8) post injection and analyzed with two-tailed Student’s paired t-test. The neuroprotective impact of ibudilast in NMDA damage was evaluated with multiple doses of intraocular ibudilast (4.5 mg/mL to 1x10^-6 mg/mL) or vehicle control (n=4/group). Chick eyes were enucleated at day 1. Cell death was measured with TUNEL assay and statistical analysis was done with Tukey HSD testing in JMP.

Results : Intraocular ibudilast toxicity testing showed no change in retinal thickness measurements after ibudilast compared to control at both 1 day and 21 days post injection. There was no significant difference in TUNEL+ cells/mm² of retina between ibudilast treated and control eyes (average 15.7±21.5 vs 2.4±5.3 respectively, p=0.25). In the NMDA retinal damage model, NMDA treated eyes showed cell death in the INL while ibudilast showed significantly reduced TUNEL as compared to controls at all doses tested (p≤0.0001). Ibudilast 1x10^-5 mg/mL showed the most difference from NMDA only in TUNEL+ cells/mm² (759.4±298.6 vs 3624.9 ±449.5, p≤0.0001, respectively).

Conclusions : Intraocular ibudilast at the maximal soluble concentration did not cause any signs of retinal toxicity, while it showed neuroprotection at several doses in the chick NMDA retinal damage model. Future studies should further evaluate its potential for clinical therapy of retinal damage.

This is a 2020 ARVO Annual Meeting abstract.