July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Connexin hemichannel block shuts down inflammation in an animal model of chronic diabetic retinopathy to improve structural and functional outcomes
Author Affiliations & Notes
  • Colin R Green
    Ophthalmology, Univ of Auckland, Auckland, New Zealand
  • Mohd N Mat Nor
    School of Optometry, University of Auckland, Auckland, New Zealand
  • Odunayo O Mugisho
    Ophthalmology, Univ of Auckland, Auckland, New Zealand
  • Ilva D Rupenthal
    Ophthalmology, Univ of Auckland, Auckland, New Zealand
  • David M Squirrell
    Ophthalmology, Univ of Auckland, Auckland, New Zealand
  • Monica L Acosta
    School of Optometry, University of Auckland, Auckland, New Zealand
  • Footnotes
    Commercial Relationships   Colin Green, OcuNexus Therapeutics Inc. (I), OcuNexus Therapeutics Inc. (C), OcuNexus Therapeutics Inc. (P); Mohd Mat Nor, None; Odunayo Mugisho, None; Ilva Rupenthal, None; David Squirrell, None; Monica Acosta, None
  • Footnotes
    Support  Buchanan Ocular Therapeutics Unit, New Zealand Health Lotteries Research Fund, Auckland Medical Research Foundation (1117015), Malaysia Ministry of Higher Education PhD Scholarship to MNMN. CRG is the W&B Hadden Professor of Ophthalmology
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2784. doi:
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      Colin R Green, Mohd N Mat Nor, Odunayo O Mugisho, Ilva D Rupenthal, David M Squirrell, Monica L Acosta; Connexin hemichannel block shuts down inflammation in an animal model of chronic diabetic retinopathy to improve structural and functional outcomes. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2784.

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

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Abstract

Purpose : Open Connexin43 (Cx43) hemichannels release ATP which can activate, amplify and perpetuate the NLRP3 inflammasome pathway underlying chronic inflammatory diseases, including diabetic retinopathy, and cause a loss of vascular integrity. A spontaneously diabetic strain of Sprague Dawley (SD) rats has been shown to develop micro and macroaneurysms, with vessel leak confirmed with Evans blue dye perfusion, and concomitant attenuation of retinal function using electroretinography (ERG). Using an oral hemichannel blocker, Xiflam (tonabersat), we sought to evaluate the potential role of hemichannel block in the treatment of diabetic retinopathy.

Methods : Diabetic rats with aneurysms, confirmed using optical coherence tomography (OCT), and reduced ERG activity at week 5 were split into two groups; one fed once daily with Xiflam (0.28mg/kg) for 14 days, one fed vehicle only (peanut butter). At week 8 animals were reassessed with OCT and ERG and retinas collected for immunohistochemical labelling with markers of Cx43, GFAP (astrocyte and Müller cell hyperreactivity) and Iba1 (microglia).

Results : Diabetic rats had elevated blood glucose levels of 16.85±0.63mmol/L compared to normal SD rats (6.37mmol/L) (p<0.001), and lower mean body weight (179.6 vs 198.2g). Xiflam treated diabetic rats had fewer and smaller retinal aneurysms compared to untreated animals. There was reduced GFAP labelling in Müller cells but intense labelling in untreated animals (p<0.001), and reduced Iba1 positive cell numbers (p<0.001) and Cx43 (p<0.001), both back to normal levels. Retinal function (ERG mixed a-wave, mixed b-wave, Rod PIII, PII and cone PII amplitudes) was reduced (p<0.001 for intensities above 0.1 log cd.s/m2 for mixed a-wave and all intensities for mixed b-wave) at 5 weeks but restored to normal levels after Xiflam treatment; retinal function of untreated animals continued to decline.

Conclusions : Cx43 hemichannel block is known to reduce the release of inflammatory cytokines in the inflammasome pathway, including VEGF. In this model of diabetes, oral Xiflam reduced aneurysms, reduced inflammation and promoted recovery of ERG activity. Targeting Cx43 hemichannels offers potential to break the inflammatory cycle and preserve vascular integrity in diabetic retinopathy, with implications for other chronic retinal diseases.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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