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Involvement of caspase-6 and caspase-8 in neuronal apoptosis and the regenerative failure of injured retinal ganglion cells.

Abstract
To promote functional recovery after CNS injuries, it is crucial to develop strategies that enhance both neuronal survival and regeneration. Here, we report that caspase-6 is upregulated in injured retinal ganglion cells and that its inhibition promotes both survival and regeneration in these adult CNS neurons. Treatment of rat retinal whole mounts with Z-VEID-FMK, a selective inhibitor of caspase-6, enhanced ganglion cell survival. Moreover, retinal explants treated with this drug extended neurites on myelin. We also show that caspase-6 inhibition resulted in improved ganglion cell survival and robust axonal regeneration following optic nerve injury in adult rats. The effects of Z-VEID-FMK were similar to other caspase inhibitory peptides including Z-LEHD-FMK and Z-VAD-FMK. In searching for downstream effectors for caspase-6, we identified caspase-8, whose expression pattern resembled that of caspase-6 in the injured eye. We then showed that caspase-8 is activated downstream of caspase-6 in the injured adult retina. Furthermore, we investigated the role of caspase-8 in RGC apoptosis and regenerative failure both in vitro and in vivo. We observed that caspase-8 inhibition by Z-IETD-FMK promoted survival and regeneration to an extent similar to that obtained with caspase-6 inhibition. Our results indicate that caspase-6 and caspase-8 are components of a cellular pathway that prevents neuronal survival and regeneration in the adult mammalian CNS.
AuthorsPhilippe P Monnier, Philippe M D'Onofrio, Mark Magharious, Adam C Hollander, Nardos Tassew, Kinga Szydlowska, Michael Tymianski, Paulo D Koeberle
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 31 Issue 29 Pg. 10494-505 (Jul 20 2011) ISSN: 1529-2401 [Electronic] United States
PMID21775595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt
  • Enzyme Inhibitors
  • GAP-43 Protein
  • Stilbamidines
  • Cholera Toxin
  • Caspase 6
  • Caspase 8
Topics
  • Animals
  • Animals, Newborn
  • Apoptosis (drug effects, physiology)
  • Axons (drug effects)
  • Caspase 6 (metabolism)
  • Caspase 8 (metabolism)
  • Cell Survival (drug effects)
  • Cholera Toxin
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Female
  • GAP-43 Protein (metabolism)
  • Injections, Intraocular (methods)
  • Male
  • Myelin Sheath (metabolism)
  • Nerve Regeneration (drug effects, physiology)
  • Optic Nerve Injuries (pathology)
  • Organ Culture Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Retinal Ganglion Cells (drug effects, enzymology, pathology)
  • Retrograde Degeneration (prevention & control)
  • Stilbamidines

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