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Cortisol promotes survival and regeneration of axotomised retinal ganglion cells and enhances effects of aurintricarboxylic acid

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Abstract

Background

Neuroprotection is essential for repair processes after a traumatic insult in the central nervous system. We have demonstrated previously significant neuroprotective properties of the anti-apoptotic drug aurintricarboxylic acid in the model of axotomised retinal ganglion cells. Glucocorticoids are widely used to treat injuries of the nervous system. Due to the anti-inflammatory and microglia-inhibiting properties of glucocorticoids, we studied the neuroprotective effects of intravitreally administered cortisol after an optic nerve cut.

Methods

Ninety-eight adult Sprague–Dawley rats were used in this study. The optic nerve was cut intra-orbitally. Either vehicle or compound solution was injected intravitreally. Fluorescent dye was put onto the optic nerve stump to label retinal ganglion cells retrogradely. Retinal whole mounts were prepared 2 weeks after axotomy, and surviving retinal ganglion cells were counted.

Results

Two weeks after axotomy, up to 50±7% of all retinal ganglion cells survived if cortisol was injected into the eye compared with 17±5% survival if only vehicle solution was injected. The neuroprotective effects of aurintricarboxylic acid (43±5% survival) could be further enhanced if combined with cortisol (up to 61±5% survival). Regeneration of cut retinal ganglion cell axons into a peripheral nerve graft could also be enhanced by an intravitreal injection of cortisol (169±42 regenerating retinal ganglion cells per mm2 vs. 73±12 cells per mm2 after vehicle injection). The increase was not as high as with aurintricarboxylic acid (192±40 cells per mm2), although more retinal ganglion cells survived with cortisol. This indicates that neuronal survival alone is not sufficient for subsequent axonal regeneration. Nevertheless, regeneration could be markedly increased if aurintricarboxylic acid and cortisol were combined (308±72 cells per mm2).

Conclusions

Whereas aurintricarboxylic acid seems to act directly on lesioned retinal ganglion cells, cortisol seems to act on the glial environment, as indicated by microglial cell morphology and enhanced glial fibrillary acidic protein expression. The results show that both neuroprotection and regeneration can be enhanced by the combination of two simple compounds acting on different sites.

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Acknowledgements

This study was supported by the grant no. 01 Ko 9805/7 from the German Federal Ministry for Education and Research (BMBF) and by a grant from the BMBF (no. 01 KS 9604/0) and the Interdisciplinary Centre of Clinical Research Münster (IZKF Project No. 3 F7). W. Lagrèze and R. Naskar are acknowledged for their critical reading of the manuscript and linguistic help respectively. I. Romann is acknowledged for performing immunohistochemistry and M. Langkamp-Flock for Western blot analysis respectively.

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  1. Department of Experimental Ophthalmology, University of Münster Eye Hospital, Domagkstrasse 15, 48149, Münster, Germany

    Peter Heiduschka & Solon Thanos

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  1. Peter Heiduschka
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  2. Solon Thanos
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Correspondence to Peter Heiduschka.

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Heiduschka, P., Thanos, S. Cortisol promotes survival and regeneration of axotomised retinal ganglion cells and enhances effects of aurintricarboxylic acid. Graefe's Arch Clin Exp Ophthalmo 244, 1512–1521 (2006). https://doi.org/10.1007/s00417-005-0164-7

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