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 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.
Medical Subject Headings
Administration, Intranasal; Aldehydes (pharmacology); Animals; Brain Infarction (drug therapy, etiology); Caspase 6 (deficiency, physiology); Caspase 9 (metabolism); Caspase Inhibitors; Cysteine Proteinase Inhibitors (therapeutic use); Disease Models, Animal; Enzyme Inhibitors (therapeutic use); Hippocampus (metabolism, pathology); Humans; In Vitro Techniques; Infarction, Middle Cerebral Artery (complications, drug therapy, pathology); Inhibitor of Apoptosis Proteins (chemistry, genetics, therapeutic use); Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins (metabolism); Nervous System Diseases (drug therapy, etiology, pathology); Neurons (pathology); PTEN Phosphohydrolase (chemistry, genetics, therapeutic use); Rats; Rats, Wistar; Time Factors
The Journal of neuroscience : the official journal of the Society for Neuroscience
Digital Object Identifier (DOI)
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, William H.; Salvesen, Guy S.; Connolly, E Sander; and Troy, Carol M., "Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke" (2011). Translational Neuroscience. 2115.