Tonabersat Inhibits Connexin43 Hemichannel Opening and Inflammasome Activation in an In Vitro Retinal Epithelial Cell Model of Diabetic Retinopathy

• Published in: International journal of molecular sciences 2020-12, Vol.22 (1), p.298
• Main Authors: Lyon, Heather, Shome, Avik, Rupenthal, Ilva D, Green, Colin R, Mugisho, Odunayo O
• Format: Article
• Language: English
• Subjects: Caspase-1; Complex formation; Connexin 43; connexin43; Cytokines; Diabetes; Diabetes mellitus; Diabetic retinopathy; Disease; hemichannels; Hyperglycemia; IL-1β; Immunohistochemistry; inflammasome; Inflammasomes; Inflammation; Interleukin 18; Interleukin 6; Labeling; Peptides; Proteins; Retina; Retinal pigment epithelium; Retinopathy; Tonabersat; Tumor necrosis factor-α; Vascular endothelial growth factor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22010298

This study was undertaken to evaluate the connexin hemichannel blocker tonabersat for the inhibition of inflammasome activation and use as a potential treatment for diabetic retinopathy. Human retinal pigment epithelial cells (ARPE-19) were stimulated with hyperglycemia and the inflammatory cytokines IL-1β and TNFα in order to mimic diabetic retinopathy molecular signs in vitro. Immunohistochemistry was used to evaluate the effect of tonabersat treatment on NLRP3, NLRP1, and cleaved caspase-1 expression and distribution. A Luminex cytokine release assay was performed to determine whether tonabersat affected proinflammatory cytokine release. NLRP1 was not activated in ARPE-19 cells, and IL-18 was not produced under disease conditions. However, NLRP3 and cleaved caspase-1 complex formation increased with hyperglycemia and cytokine challenge but was inhibited by tonabersat treatment. It also prevented the release of proinflammatory cytokines IL-1β, VEGF, and IL-6. Tonabersat therefore has the potential to reduce inflammasome-mediated inflammation in diabetic retinopathy.