Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke.
J Neurosci
; 31(24): 8894-904, 2011 Jun 15.
Article
em En
| MEDLINE
| ID: mdl-21677173
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Infarto da Artéria Cerebral Média
/
Inibidores Enzimáticos
/
Proteínas Inibidoras de Apoptose
/
Caspase 6
/
Doenças do Sistema Nervoso
/
Neurônios
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article