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Tyler Heisler-Taylor, Elizabeth G Urbanski, Sumaya Hamadmad, Claire Landreth, Hailey Wilson, Julie Racine, Colleen M Cebulla; MIF inhibition improves retinal function in NMDA mediated excitotoxic damage. Invest. Ophthalmol. Vis. Sci. 2022;63(7):3181 – F0455.
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© ARVO (1962-2015); The Authors (2016-present)
Inhibition of macrophage migration inhibitory factor (MIF) has shown promise protecting retinal neurons in excitotoxic retinal damage models. We evaluated the ability of three MIF inhibitors (MIFi) to improve electroretinography (ERG) function in the chick excitotoxic retinal damage model.
Experiments were performed under an IACUC approved protocol. White leghorn chicks (n=3/group) were given intravitreal injections with NMDA (500nmol) at day 0 (D0) plus one of three different MIFi: ibudilast, AV1013, or CPSI-1306 at 1.0 mg/ml or vehicle (sterile water). Injections of MIFi and vehicle was performed on D-1, and D0. ERG waveforms were captured between D10-D14 with the Celeris ERG system. Light adapted ERGs and oscillatory potentials were captured with flash intensities between 0.05 and 25 cd*s/m2. Additionally, 20Hz flicker and long flash ERGs were recorded. Statistics were calculated in Graphpad PRISM using ANOVA with Tukey and Dunnett multiple comparison testing. A p-value ≤ 0.05 was considered statistically significant.
ERG measurements resulted in no significant differences between MIFi-treated and vehicle-treated NMDA-damaged eyes in the CPSI-1306 and AV1013 groups. Ibudilast treatment resulted in significant improvement in two groups: the ERG b-wave and the long flash ERG bipolar-ON wave. NMDA-damaged eyes treated with ibudilast were found to have significantly higher b-wave amplitudes at 3, 8, and 13 cd*s/m2 (177.24±47.04 µV vs 278.60±61.78 µV, p=0.0049; 192.08±64.39 µV vs 279.90±40.62 µV, p=0.0173; 183.16±66.67 µV vs 265.00±27.23 µV, p=0.0288; NMDA+vehicle vs NMDA+ibudilast, respectively). The ON waves were also improved due to statistically higher amplitudes (11.09±5.26 µV vs 35.54±22.68 µV, p=0.0170; NMDA+vehicle vs NMDA+ibudlast). Both of these waveform groups correspond to inner retinal neurons, which are most susceptible to excitotoxic damage caused by NMDA.
Ibudilast is approved in Japan for neurologic and inflammatory indications and is in clinical trials for multiple sclerosis in the US. Preliminary results show ibudilast is promising for excitotoxic retinal damage prevalent in many retinal disorders like blast injury, diabetic retinopathy, vein occlusion and retinal ischemia.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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