Cyclosporine A Protects Retinal Explants against Hypoxia

• Published in: International journal of molecular sciences 2021-10, Vol.22 (19), p.10196
• Main Authors: Schnichels, Sven, Schultheiss, Maximilian, Klemm, Patricia, Blak, Matthias, Herrmann, Thoralf, Melchinger, Marion, Bartz-Schmidt, Karl-Ulrich, Löscher, Marina, Zeck, Günther, Spitzer, Martin Stehphan, Hurst, José
• Format: Article
• Language: English
• Subjects: Apoptosis; Biocompatibility; Brn-3 protein; cyclosporine A; Cyclosporins; Diabetic retinopathy; Explants; Eye (anatomy); Glaucoma; Glia; Homeobox; Hypoxia; Immunohistochemistry; Immunosuppressive agents; In vivo methods and tests; ischemia; Microglia; Neuroprotection; Oxidative stress; Protein 3a; Retina; Retinal ganglion cells; Thickness
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms221910196

The retina is a complex neurological tissue and is extremely sensitive to an insufficient supply of oxygen. Hypoxia plays a major role in several retinal diseases, and often results in the loss of cells that are essential for vision. Cyclosporine A (CsA) is a widely used immunosuppressive drug. Furthermore, treatment with CsA has neuroprotective effects in several neurologic disorders. No data are currently available on the tolerated concentration of CsA when applied to the retina. To reveal the most effective dose, retinal explants from rat eyes were exposed to different CsA concentrations (1–9 µg/mL). Immunohistochemistry with brain-specific homeobox/POU domain protein 3a (Brn3a) and TUNEL staining was performed to determine the percentage of total and apoptotic retinal ganglion cells (RGCs), as well as the responses of micro- and macroglial cells. Furthermore, optical coherence tomography (OCT) scans were performed to measure the changes in retinal thickness, and recordings with multielectrode array (MEA) were performed to evaluate spontaneous RGC spiking. To examine the neuroprotective effects, retinas were subjected to a hypoxic insult by placing them in a nitrogen-streamed hypoxic chamber prior to CsA treatment. In the biocompatibility tests, the different CsA concentrations had no negative effect on RGCs and microglia. Neuroprotective effects after a hypoxic insult on RGCs was demonstrated at a concentration of 9 µg/mL CsA. CsA counteracted the hypoxia-induced loss of RGCs, reduced the percentage of TUNEL+ RGCs, and prevented a decrease in retinal thickness. Taken together, the results of this study suggest that CsA can effectively protect RGCs from hypoxia, and the administered concentrations were well tolerated. Further in vivo studies are needed to determine whether local CsA treatment may be a suitable option for hypoxic retinal diseases.