Cyclosporine A Protects RGC-5 Cells From Excitotoxic Cell Death

Schultheiß, Maximilian; Schnichels, Sven; Młyńczak, Tomasz; Dipl-Ing, Johanna Hofmann; Bartz‐Schmidt, Karl Ulrich; Szurman, Peter; Spitzer, Martin S.

doi:10.1097/ijg.0000000000000040

Cited by 7 publications

(6 citation statements)

References 33 publications

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“…In summary, 9 µg/mL CsA presented good biocompatibility and induced a neuroprotective effect after hypoxic treatment. The observed neuroprotective effect is in line with the previously published data [ 25 , 26 ]. Thus, CsA might have additional therapeutic potential in the treatment of glaucoma or ischemic retinal vascular diseases like diabetic retinopathy or retinal vein occlusion.…”

Section: Discussionsupporting

confidence: 93%

“…In retinal hypoxia after intraocular pressure elevation, CsA also proved to be a potent neuroprotective agent [ 25 ]. In this work, concentrations of 1, 3, 6, and 9 µg/mL were chosen since higher concentrations induced a decrease in cell viability in a previously published study using RGC-5 cells [ 26 ]. In a study by Kaminska et al, slightly higher concentrations (8–40 µM) led to the apoptosis of mixed neuronal/glial cultures, where TUNEL + staining was observed only in neurons while astrocytes were unaffected [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, inhibition of CypD by CsA treatment promotes RGC survival and blocks cell death in ischemic retinal injury [ 25 ]. Additionally, CsA has been shown to induce a dose-dependent reduction in the expression and activity of caspase 3 [ 25 , 26 ]. Results consistent with the work of Kim et al regarding the survival of RGCs and activation of macroglia were noted.…”

Section: Discussionmentioning

confidence: 99%

“…In prior studies, we used the RGC-5 cell line and administered CsA directly to the RGC-5 cell culture [ 26 ]. In those experiments, 9 µg/mL exhibited the best neuroprotective results in cells stressed with 10 mM glutamate for 24 h. Glutamate induced a significant decrease in overall cell viability.…”

Section: Introductionmentioning

confidence: 99%

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Cyclosporine A Protects Retinal Explants against Hypoxia

Schnichels

Schultheiß

Klemm

et al. 2021

IJMS

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cyclosporine A Protects Retinal Explants against Hypoxia

Schnichels

Schultheiß

Klemm

et al. 2021

IJMS

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“…Schultheiss et al 20 demonstrated that cyclosporine has a dose-dependent neuroprotective effect that enhances the survival of rat ganglion cells in culture when cyclosporine concentrations exceed 1 lg/mL. The minipigs used for our study had been under cyclosporine treatment; however, we found that the spread of ganglion cell activity was equally large in the retinas of sham-treated pigs (no cyclosporine, data points to the left of the dashed vertical line in Fig.…”

Section: Long Retinal Ganglion Cell Survival By Slow Cooling To 48ccontrasting

confidence: 48%

Hypothermia Promotes Survival of Ischemic Retinal Ganglion Cells

Reinhard

Marion

Gustafsson

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Reinhard K, Mutter M, Gustafsson E, et al. Hypothermia promotes survival of ischemic retinal ganglion cells. Invest Ophthalmol Vis Sci. 2016;57:658-663. DOI:10.1167/ iovs.15-17751 PURPOSE. Ischemic stroke in retinal arteries leads to death of neural tissue and ultimately to blindness. The retina is known to die within 4 hours after onset of ischemia. It is debated whether hypothermia might increase the time window for medical treatment and thereby the chance of recovering sight. In order to characterize the time course of cell death during ischemia and potential beneficial effects of hypothermia in more detail, we investigated the survival of ganglion cells in ischemic pig and human retina as a function of time and temperature.METHODS. Eyes were obtained from minipigs and from human donors post mortem. Enucleated minipig eyes were stored for defined durations at three different temperatures (378C, 218C, and 48C). In order to assess the viability of the tissue, we measured ganglion cell activity (spiking) with multielectrode arrays. RESULTS.Minipig retinal ganglion cell function was severely compromised after 2 hours of ischemia at body temperature. After 4 hours, ganglion cells did not fire action potentials anymore. However, at 218C, ganglion cell activity was maintained under ischemic conditions for up to 12 hours, and for at least 50 hours at 48C. In postmortem human retina, we recorded ganglion cell activity in retinas received up to 27 hours after death.CONCLUSIONS. Our results demonstrate that hypothermia greatly increases survival of retinal ganglion cells exposed to ischemia. These results might be relevant for the future treatment of retinal ischemia.

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