June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Therapeutic Intervention of p75NTR With LM11A-31 Protects Against Systemic and Retinal Inflammation And Visual Impairment In A Model of Diabetic Retinopathy
Author Affiliations & Notes
  • Azza B El-Remessy
    Surgery, University of Illinois at Chicago, Chicago, Illinois, United States
    Augusta Biomedical Res Corp, Augusta, Georgia, United States
  • Riyaz Mohamed
    Augusta Biomedical Res Corp, Augusta, Georgia, United States
    Augusta University, Augusta, Georgia, United States
  • Laura Pearson
    Augusta Biomedical Res Corp, Augusta, Georgia, United States
  • Frank Longo
    Neurology, Stanford University, San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Azza El-Remessy, None; Riyaz Mohamed, None; Laura Pearson, None; Frank Longo, PharmatrophiX (I)
  • Footnotes
    Support  EY022408
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1758. doi:
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      Azza B El-Remessy, Riyaz Mohamed, Laura Pearson, Frank Longo; Therapeutic Intervention of p75NTR With LM11A-31 Protects Against Systemic and Retinal Inflammation And Visual Impairment In A Model of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1758.

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

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Abstract

Purpose : Over the past decade, our work established the critical contribution of proNGF, proform of the nerve growth factor and its receptor p75NTR in mediating diabetic retinopathy. Deletion of p75NTR preserved the barrier function, prevented inflammatory mediators and microvascular degeneration in diabetic retinas. This study aims to examine the therapeutic efficacy of LM11A-31, a small-molecule p75NTR modulator and proNGF antagonist, in preventing diabetes-associated systemic and retinal inflammation as well as visual activity in a model of acute ischemia/reperfusion.

Methods : Male C57BL/6 J (WT) mice were rendered diabetic by streptozotocin, then after 4-weeks mice were randomized to receive LM11A-31 (50 mg/Kg/2days) or saline for an additional 12-weeks. Additional group of mice underwent ischemia/reperfusion (IR) injury by increasing intraocular pressure for 40 min, followed by reperfusion. 2 days post IR injury, mice were randomized to receive received oral gavage of LM11A-31 (50 mg/Kg/2days) or saline for an additional 12-days. Urine, serum, and tissues were harvested for biochemical analyses. Visual function was assessed using visual clue-water maize. The visual test was performed after 1, 3, 6, 9, 12 and 15 days post-ischemic injury.

Results : Diabetes induced significant increases in systemic inflammation evident by significant increases in the Urinary Albumin excretion to Creatinine (UAC) ratio and enhanced level of IL-1β in serum and urine and in both retina and kidney compared to controls (P<0.05, n=5-6). Intervention with LM11A-31 did not alter body weight or glycemic level in control or diabetic mice. Intervention with LM11A-31 significantly reduced diabetes-induced inflammation and UAC ratio (P<0.05, n=5-6). Using the ischemia/reperfusion model, vehicle-treated IR mice exhibited visual dysfunction evident by significantly delayed time to reach the platform compared to shams (P<0.05, n=7-9). Intervention with LM11A-31 significantly improved visual function in IR-mice compared to vehicle-treated mice after 6-days of initial insult and persisted till day-15.

Conclusions : Therapeutic intervention of p75NTR signaling using LM11A-31, an orally bioavailable receptor modulator, offers an effective, safe and non-invasive strategy for treating diabetes-associated inflammation and visual impairment, a major cause of blindness in diabetes.

This is a 2020 ARVO Annual Meeting abstract.

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