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Intravitreal injection of lipoamino acid-modified connexin43 mimetic peptide enhances neuroprotection after retinal ischemia

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Abstract

Optic neuropathy is associated with retinal ganglion cell (RGC) loss leading to optic nerve damage and visual impairment. Recent research has shown that transient block of connexin43 (Cx43) hemichannels by a Cx43 mimetic peptide (MP), Peptide5, delivered systemically or by intravitreal injection after retinal ischemia inhibits uncontrolled hemichannel opening to provide significantly reduced vessel leak and inflammation as well as significantly enhanced RGC survival. We have previously shown, in vitro, that a chemically modified C12-C12-Cx43 MP has a twofold greater half-life in bovine vitreous (ex vivo) than the native peptide. The present study investigated the ability of intravitreally injected, chemically modified C12-C12-Cx43 MP to further enhance RGC survival in a rat retinal ischemia-reperfusion model. Intravitreally injected native Cx43 MP or C12-C12-Cx43 MP both minimized vessel leak, reduced inflammation, and protected RGC after ischemic injury. However, the modified C12-C12-Cx43 MP, with its prolonged vitreous stability, showed significantly lower levels of Cx43 expression post-injury, with a trend towards a greater reduction in vessel leak and further RGC protection, suggesting that these molecules may be a clinically relevant neuroprotective tool in the treatment of optic neuropathy.

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Acknowledgments

The authors would like to thank Professor Toth’s group for their support during the synthesis and modification of the Cx43 MP. We acknowledge the Auckland Medical Research Foundation (1210003) for the financial support in the form of a doctoral scholarship for Ying-Shan Chen and the Buchanan Charitable Foundation and the Health Research Council of New Zealand (13/692 and 14/018) for their financial support.

Conflict of interest

Professor Colin Green is a founding scientist of CoDa Therapeutics, Inc. USA, which holds intellectual property for the use of connexin peptides to regulate gap junction channels for the treatment of ocular disease.

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Authors and Affiliations

  1. Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Ying-Shan Chen & Ilva D. Rupenthal

  2. Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Ying-Shan Chen, Colin R. Green, Rebecca Teague, Joshua Perrett, Helen V. Danesh-Meyer & Ilva D. Rupenthal

  3. School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia

    Istvan Toth

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  1. Ying-Shan Chen
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Correspondence to Ilva D. Rupenthal.

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Chen, YS., Green, C.R., Teague, R. et al. Intravitreal injection of lipoamino acid-modified connexin43 mimetic peptide enhances neuroprotection after retinal ischemia. Drug Deliv. and Transl. Res. 5, 480–488 (2015). https://doi.org/10.1007/s13346-015-0249-8

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