Cortisol promotes survival and regeneration of axotomised retinal ganglion cells and enhances effects of aurintricarboxylic acid.
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.
Department of Experimental Ophthalmology, University of Münster Eye Hospital, Domagkstrasse 15, 48149 Münster, Germany. peter.heiduschka@med.uni-tuebingen.de
Peter
P
Heiduschka
Solon
S
Thanos
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D001369:Axons / Q000502:physiology*; D019771:Axotomy; D015153:Blotting, Western; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006854:Hydrocortisone / Q000494:pharmacology*; D007267:Injections; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009900:Optic Nerve / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014822:Vitreous Body
D005456:Fluorescent Dyes; D005904:Glial Fibrillary Acidic Protein; D005938:Glucocorticoids; D018696:Neuroprotective Agents; D001312:Aurintricarboxylic Acid; D005974:Glutamate-Ammonia Ligase; D006854:Hydrocortisone