June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
MIF Inhibitor Ibudilast Prevents Retinal Cell Death in Chick Excitotoxic Retinal Damage Model
Author Affiliations & Notes
  • Elizabeth G Urbanski
    Ophthalmology and Visual Science, The Ohio State University, Columbus, Ohio, United States
  • Tyler N Heisler-Taylor
    Ophthalmology and Visual Science, The Ohio State University, Columbus, Ohio, United States
    Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States
  • Richard Wan
    Optometry, The Ohio State University, Columbus, Ohio, United States
    Ophthalmology and Visual Science, The Ohio State University, Columbus, Ohio, United States
  • Mohd Hussain Shah
    Ophthalmology and Visual Science, The Ohio State University, Columbus, Ohio, United States
  • Sumaya Hamadmad
    Ophthalmology and Visual Science, The Ohio State University, Columbus, Ohio, United States
  • Andrew J Fischer
    Neuroscience, The Ohio State University, Columbus, Ohio, United States
  • Abhay Satoskar
    Pathology, The Ohio State University, Columbus, Ohio, United States
  • Colleen M Cebulla
    Ophthalmology and Visual Science, The Ohio State University, Columbus, Ohio, United States
  • Footnotes
    Commercial Relationships   Elizabeth Urbanski, None; Tyler Heisler-Taylor, None; Richard Wan, None; Mohd Hussain Shah, None; Sumaya Hamadmad, None; Andrew Fischer, None; Abhay Satoskar, None; Colleen Cebulla, None
  • Footnotes
    Support  This work was supported by the Department of Defense under Award No. W81XWH1810805 and the Ohio Lions Eye Research Foundation. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the funding institutions.
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2478. doi:
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      Elizabeth G Urbanski, Tyler N Heisler-Taylor, Richard Wan, Mohd Hussain Shah, Sumaya Hamadmad, Andrew J Fischer, Abhay Satoskar, Colleen M Cebulla; MIF Inhibitor Ibudilast Prevents Retinal Cell Death in Chick Excitotoxic Retinal Damage Model. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2478.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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