Modified connexin43 mimetic peptide shows higher efficacy in reducing retinal ganglion cell loss and vessel leak after retinal ischemia

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Abstract

Purpose

Optic neuropathy is associated with retinal ganglion cell (RGC) loss leading to optic nerve damage and visual impairment. Transient block of connexin43 (Cx43) hemichannels by mimetic peptides (MP) after retinal ischemia has been shown to inhibit uncontrolled hemichannel opening and may provide improved RGC survival. However, high hydrophilicity and poor peptide stability can limit efficient delivery in a clinical setting. This study evaluated the efficacy of modified Cx43MP using a retinal ischemia reperfusion rat model.

Methods

Retinal ischemia was created in the left eye (120 mmHg for 60 min) with the right eye serving as a control and Cx43MP formulations were injected intravitreally. Evan’s blue dye was injected intraperitoneally 4 h after reperfusion to visualize vessel leak using confocal microscopy. Retinal whole mounts were also labeled with Cx43, GFAP and Brn3a antibodies to quantify Cx43 and RGC densities.

Results

Intravitreal injection of native and modified Cx43MP resulted in significantly reduced Cx43 levels compared to untreated eyes 8 h after ischemia, with Cx43MP containing two C12-lipoamino acid groups reducing Cx43 counts almost down to baseline level. A similar trend was seen for RCG counts with the modified Cx43MP resulting in >93% RCG survival after 28 days compared to <70% for untreated eyes. Vessel leak was also noticeably reduced in Cx43MP treated eyes.

Conclusion

C12-lipoamino acid conjugation to Cx43MP increased peptide stability and may have also resulted in better tissue permeability, improving the overall efficacy of Cx43MP. Modified Cx43MP may therefore offer a clinically relevant treatment option for optic neuropathies.

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