Combined inhibition of Cdk5 and ROCK additively increase cell survival, but not the regenerative response in regenerating retinal ganglion cells.
CNS regeneration is limited by lesion-induced neuronal apoptosis and an environment inhibiting axonal elongation. Inhibition of ROCK has been previously shown to promote regeneration in retinal ganglion cells (RGC) whereas Cdk5 inhibition mainly promoted survival. Therefore, we have evaluated the effects of combined treatment with inhibitors of ROCK and Cdk5. We show that in vitro, the co-application of the Cdk5 inhibitor, Indolinone A, and the ROCK inhibitor, Y-27632, potentiated the survival-promoting effect of either substance alone. However, neurite outgrowth in vitro was promoted only by the presence of Y-27632, not by Indolinone A alone. In the ex vivo explant and the in vivo optic nerve crush model the combination of both inhibitors significantly increased neurite outgrowth at small distances, but this effect leveled off for longer neurites. In summary, the combined treatment with the Cdk5 inhibitor Indolinone A and the ROCK inhibitor Y-27632 results in a strong additive effect on neuronal survival, but is not able to increase the regenerative response beyond the effect of the ROCK inhibitor.
Bermel
Christina
C
Department of Neurology, University Medicine Göttingen, Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Tönges
Lars
L
Planchamp
Véronique
V
Gillardon
Frank
F
Weishaupt
Jochen H
JH
Dietz
Gunnar P H
GP
Bähr
Mathias
M
Lingor
Paul
P
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000502:physiology / Q000648:ultrastructure; D010770:Phosphotransferases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000577:Amides; C492235:Cdk5r1 protein, rat; D004791:Enzyme Inhibitors; D007211:Indoles; C503753:Indolinone A; D009419:Nerve Tissue Proteins; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014404:Tubulin; C089495:neuronal Cdk5 activator (p25-p35); C108830:Y 27632; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; C495907:Cdk5 protein, rat; D020928:Mitogen-Activated Protein Kinases