Connexin Hemichannel Block Using Orally Delivered Tonabersat Improves Outcomes in Animal Models of Retinal Disease
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ORIGINAL ARTICLE
Connexin Hemichannel Block Using Orally Delivered Tonabersat Improves Outcomes in Animal Models of Retinal Disease Mohd Nasir Mat Nor 1,2 & Ilva D. Rupenthal 3,4 & Colin R. Green 4 & Monica L. Acosta 1
# The American Society for Experimental NeuroTherapeutics, Inc. 2019
Abstract 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. Key Words Macular degeneration . diabetic retinopathy . tonabersat . inflammasome . retina . choroid . Connexin43 . inflammation
Introduction Tonabersat, a novel benzopyran compound (cis-6-acetyl4S-(3-chloro-4-fluoro-benzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo [b]pyrane-3 S-ol (SB-220453), was originally clinically evaluated for the treatment of migraine [1]. A previous study had indicated that neuronal-glial Connexin26 gap junctions might play a role in cortical * Monica L. Acosta [email protected] 1
School of Optometry and Vision Science and New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
2
Faculty of Medicine, University of Sultan Zainal Abidin, Kuala Terengganu, Malaysia
3
Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, and New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
4
Department of Ophthalmology and New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
spreading depression associated with migraine [2, 3], with tonabersat said to reduce Connexin26 protein expression [4–6]. Controlled clinical trials showed that the compound is well tolerated with no significant safety concerns [3, 7]. Clinical evaluations included monitoring of blood pressure and heart rate [
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