title: Targeting caspase-6 and caspase-8 to promote neuronal survival following ischemic stroke.
abstract: Previous studies show that caspase-6 and caspase-8 are involved in neuronal apoptosis and regenerative failure after trauma of the adult central nervous system (CNS). In this study, we evaluated whether caspase-6 or -8 inhibitors can reduce cerebral or retinal injury after ischemia. Cerebral infarct volume, relative to appropriate controls, was significantly reduced in groups treated with caspase-6 or -8 inhibitors. Concomitantly, these treatments also reduced neurological deficits, reduced edema, increased cell proliferation, and increased neurofilament levels in the injured cerebrum. Caspase-6 and -8 inhibitors, or siRNAs, also increased retinal ganglion cell survival at 14 days after ischemic injury. Caspase-6 or -8 inhibition also decreased caspase-3, -6, and caspase-8 cleavage when assayed by western blot and reduced caspase-3 and -6 activities in colorimetric assays. We have shown that caspase-6 or caspase-8 inhibition decreases the neuropathological consequences of cerebral or retinal infarction, thereby emphasizing their importance in ischemic neuronal degeneration. As such, caspase-6 and -8 are potential targets for future therapies aimed at attenuating the devastating functional losses that result from retinal or cerebral stroke.
authors.affiliation: Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Canada.|Toronto Western Research Institute, Toronto Western Hospital, Toronto, Canada.
authors.forename: A P
authors.initials: AP
authors.lastname: Shabanzadeh
authors.affiliation: Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Canada.|Graduate Department of Rehabilitation Science, University of Toronto, Toronto, Canada.
authors.forename: P M
authors.initials: PM
authors.lastname: D'Onofrio
authors.affiliation: Toronto Western Research Institute, Toronto Western Hospital, Toronto, Canada.|Departments of Physiology, University of Toronto, Toronto, Canada.
authors.forename: P P
authors.initials: PP
authors.lastname: Monnier
authors.affiliation: Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Canada.|Graduate Department of Rehabilitation Science, University of Toronto, Toronto, Canada.
authors.forename: P D
authors.initials: PD
authors.lastname: Koeberle
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053178:Caspase 6 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D005260:Female; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012160:Retina / Q000473:pathology; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D061945:Caspase Inhibitors; D018696:Neuroprotective Agents; D053178:Caspase 6; D053181:Caspase 8