title: Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke.
abstract: Despite extensive research to develop an effective neuroprotective strategy for the treatment of ischemic stroke, therapeutic options remain limited. Although caspase-dependent death is thought to play a prominent role in neuronal injury, direct evidence of active initiator caspases in stroke and the functional relevance of this activity have not previously been shown. Using an unbiased caspase-trapping technique in vivo, we isolated active caspase-9 from ischemic rat brain within 1 h of reperfusion. Pathogenic relevance of active caspase-9 was shown by intranasal delivery of a novel cell membrane-penetrating highly specific inhibitor for active caspase-9 at 4 h postreperfusion (hpr). Caspase-9 inhibition provided neurofunctional protection and established caspase-6 as its downstream target. The temporal and spatial pattern of expression demonstrates that neuronal caspase-9 activity induces caspase-6 activation, mediating axonal loss by 12 hpr followed by neuronal death within 24 hpr. Collectively, these results support selective inhibition of these specific caspases as an effective therapeutic strategy for stroke.
authors.affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. nea2107@columbia.edu
authors.forename: Nsikan
authors.initials: N
authors.lastname: Akpan
authors.forename: Esther
authors.initials: E
authors.lastname: Serrano-Saiz
authors.forename: Brad E
authors.initials: BE
authors.lastname: Zacharia
authors.forename: Marc L
authors.initials: ML
authors.lastname: Otten
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ducruet
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Snipas
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Velloza
authors.forename: Greg
authors.initials: G
authors.lastname: Cohen
authors.forename: Sergeyi A
authors.initials: SA
authors.lastname: Sosunov
authors.forename: William H
authors.initials: WH
authors.lastname: Frey
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
authors.forename: Carol M
authors.initials: CM
authors.lastname: Troy
mesh_terms: D000281:Administration, Intranasal; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D053178:Caspase 6 / Q000172:deficiency / Q000502:physiology*; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000447:Aldehydes; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D009419:Nerve Tissue Proteins; D051059:PTEN Phosphohydrolase; D053178:Caspase 6; D053453:Caspase 9; C027576:4-hydroxy-2-nonenal