June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Cannabinoid Receptor 2 Agonist HU-308 Demonstrates Therapeutic Potential in Inflammatory Diabetic Retinopathy Models
Author Affiliations & Notes
  • Cayla Ontko
    Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
  • Minjae J Kim
    Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Taylor E Smith
    Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Gary W. McCollum
    Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Rong Yang
    Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • John Penn
    Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Footnotes
    Commercial Relationships   Cayla Ontko, None; Minjae Kim, None; Taylor Smith, None; Gary McCollum, None; Rong Yang, None; John Penn, None
  • Footnotes
    Support  NIH grant R01 EY007533 and T32 EY021453
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 3012. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Cayla Ontko, Minjae J Kim, Taylor E Smith, Gary W. McCollum, Rong Yang, John Penn; Cannabinoid Receptor 2 Agonist HU-308 Demonstrates Therapeutic Potential in Inflammatory Diabetic Retinopathy Models. Invest. Ophthalmol. Vis. Sci. 2021;62(8):3012.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Increased retinal and vitreous levels of inflammatory cytokines are observed in early diabetic retinopathy (DR) progression and are experimentally linked to several hallmark DR features, including leukostasis and vascular hyperpermeability. Cannabinoid (CB) receptor 2 agonism has been shown to decrease inflammatory cytokine production and leukocyte recruitment in various non-ocular inflammation models, suggesting that CB2 agonism could have similar therapeutic potential in DR-related inflammation. This study tested the potential of CB2-selective agonist, HU-308, to attenuate DR pathologies in response to diabetes-relevant inflammatory stimuli (DRS), including increased inflammatory cytokine expression, adhesion molecule expression, leukostasis, and vascular hyperpermeability.

Methods : Primary human Müller cells (hMC) were treated with IL-1β (1ng/ml) for 8hrs, and HU-308 (0.1uM) was added at the onset of treatment and again 4hrs later. Human retinal microvascular endothelial cells (HRMEC) were pre-treated with HU-308 (1uM) for 2hrs and TNFα (0.1ng/ml) was added for an additional 2hrs. Relative expression of inflammatory mediators and leukocyte adhesion molecules was analyzed via qRT-PCR. To investigate vascular responses in vivo, C57BL/6 mice received daily IP injections of HU-308 (5.0mg/kg) for 1wk prior to receiving an intravitreal injection of TNFα (25ng/ml). Quantitative fluorescein angiography (qFA) and leukostasis analyses were performed 6 and 12hrs later, respectively.

Results : HU-308 significantly decreased IL-1β-induced expressionof IL-1β by 29.5% (p=0.0295) in hMC. HU-308 significantly decreased TNFα-induced expression of leukocyte adhesion molecules ICAM-1 by 26.8% (p=0.0380) and E-selectin by 21.7% (p=0.0141) in hRMEC. In vivo, systemic HU-308 significantly decreased TNFα-induced leukostasis by 55.3% (p=0.0401) and TNFα-induced vascular hyperpermeability by 74.7% (p=0.0039).

Conclusions : Consistent with our hypothesis, CB2 agonism was found to decrease cellular cytokine expression and leukocyte adhesion molecule expression in response to DRS, as well as decrease leukostasis and vascular hyperpermeability in an in vivo model of acute retinal inflammation. These results demonstrate that CB2 agonism has significant therapeutic potential for preventing retinal inflammation characteristic of early DR.

This is a 2021 ARVO Annual Meeting abstract.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×