title: 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.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. pmonnier@uhnres.utoronto.ca
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Monnier
authors.forename: Philippe M
authors.initials: PM
authors.lastname: D'Onofrio
authors.forename: Mark
authors.initials: M
authors.lastname: Magharious
authors.forename: Adam C
authors.initials: AC
authors.lastname: Hollander
authors.forename: Nardos
authors.initials: N
authors.lastname: Tassew
authors.forename: Kinga
authors.initials: K
authors.lastname: Szydlowska
authors.forename: Michael
authors.initials: M
authors.lastname: Tymianski
authors.forename: Paulo D
authors.initials: PD
authors.lastname: Koeberle
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001369:Axons / Q000187:drug effects; D053178:Caspase 6 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002772:Cholera Toxin; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D056965:Injections, Intraocular / Q000379:methods; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D020221:Optic Nerve Injuries / Q000473:pathology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D012183:Retrograde Degeneration / Q000517:prevention & control; D013266:Stilbamidines
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D004791:Enzyme Inhibitors; D019922:GAP-43 Protein; D013266:Stilbamidines; D002772:Cholera Toxin; D053178:Caspase 6; D053181:Caspase 8