Journal
NEUROTHERAPEUTICS
Volume 17, Issue 1, Pages 371-387Publisher
SPRINGER
DOI: 10.1007/s13311-019-00786-5
Keywords
Macular degeneration; diabetic retinopathy; tonabersat; inflammasome; retina; choroid; Connexin43; inflammation
Funding
- New Zealand Lottery Health Research [3702828]
- Auckland UniServices Ltd. [5000293]
- Maurice and Phyllis Paykel Trust [3708721]
- New Zealand Optometric Vision Research Foundation [3717092]
- Buchanan Charitable Foundation
- Ministry of Higher Education Malaysia
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Increased Connexin43 hemichannel opening is associated with inflammasome pathway activation and inflammation in a range of pathologies including ocular disorders, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). In this study, the effect on retinal function and morphology of clinically safe doses of orally delivered tonabersat, a small molecule connexin hemichannel blocker, was investigated in the light-damaged retina animal model of dry AMD and in a spontaneous rat model of DR. Clinical parameters (fundus imaging, optical coherence tomography (OCT), and electroretinography) and inflammatory markers (immunohistochemistry for Iba-1 microglial marker, astrocyte marker glial fibrillary acidic protein, and Connexin43 protein expression) were assessed. Tonabersat treatment reduced inflammation in the retina in parallel with preservation of retinal photoreceptor function when assessed up to 3 months post light damage in the dry AMD model. In the DR model, clinical signs, including the presence of aneurysms confirmed using Evans blue dye perfusion, were reduced after daily tonabersat treatment for 2 weeks. Inflammation was also reduced and retinal electrical function restored. Tonabersat regulates assembly of the inflammasome (NLRP3) through Connexin43 hemichannel block, with the potential to reduce inflammation, restore vascular integrity and improve anatomical along with some functional outcomes in retinal disease.
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