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

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 th...

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Bibliographic Details
Published in:The Journal of neuroscience 2011-06, Vol.31 (24), p.8894-8904
Main Authors: Akpan, Nsikan, Serrano-Saiz, Esther, Zacharia, Brad E, Otten, Marc L, Ducruet, Andrew F, Snipas, Scott J, Liu, Wen, Velloza, Jennifer, Cohen, Greg, Sosunov, Sergeyi A, Frey, 2nd, William H, Salvesen, Guy S, Connolly, Jr, E Sander, Troy, Carol M
Format: Article
Language:English
Subjects:
Administration, Intranasal
Aldehydes - pharmacology
Animals
Brain Infarction - drug therapy
Brain Infarction - etiology
Caspase 6 - deficiency
Caspase 6 - physiology
Caspase 9 - metabolism
Caspase Inhibitors
Cysteine Proteinase Inhibitors - therapeutic use
Disease Models, Animal
Enzyme Inhibitors - therapeutic use
Hippocampus - metabolism
Hippocampus - pathology
Humans
In Vitro Techniques
Infarction, Middle Cerebral Artery - complications
Infarction, Middle Cerebral Artery - drug therapy
Infarction, Middle Cerebral Artery - pathology
Inhibitor of Apoptosis Proteins - chemistry
Inhibitor of Apoptosis Proteins - genetics
Inhibitor of Apoptosis Proteins - therapeutic use
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins - metabolism
Nervous System Diseases - drug therapy
Nervous System Diseases - etiology
Nervous System Diseases - pathology
Neurons - pathology
PTEN Phosphohydrolase - chemistry
PTEN Phosphohydrolase - genetics
PTEN Phosphohydrolase - therapeutic use
Rats
Rats, Wistar
Time Factors
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0698-11.2011