Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke

Nsikan Akpan, Esther Serrano-Saiz, Brad E. Zacharia, Marc L. Otten, Andrew F. Ducruet, Scott J. Snipas, Wen Liu, Jennifer Velloza, Greg Cohen, Sergeyi A. Sosunov, William H. Frey, Guy S. Salvesen, E. Sander Connolly, Carol M. Troy

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

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, weisolated 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.

Original languageEnglish (US)
Pages (from-to)8894-8904
Number of pages11
JournalJournal of Neuroscience
Volume31
Issue number24
DOIs
StatePublished - Jun 15 2011

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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