Inhibition of cysteine cathepsin B and L activation in astrocytes contributes to neuroprotection against cerebral ischemia via blocking the tBid-mitochondrial apoptotic signaling pathway.
Glia
; 62(6): 855-80, 2014 Jun.
Article
em En
| MEDLINE
| ID: mdl-24616078
ABSTRACT
The roles of cathepsins in the ischemic astrocytic injury remain unclear. Here, we test the hypothesis that activation of cathepsin B and L contributes to the ischemic astrocyte injury via the tBid-mitochondrial apoptotic signaling pathways. In the rat models of pMCAO, CA-074Me or Clik148, a selective inhibitor of cathepsin B or cathepsin L, reduced the infarct volume, improved the neurological deficits and increased the MAP2 and GFAP levels. In OGD-induced astrocyte injury, CA-074Me or Clik148 decreased the LDH leakage and increased the GFAP levels. In the ischemic cortex or OGD-induced astrocytes injury, Clik148 or CA-074Me reversed pMCAO or OGD-induced increase in active cathepsin L or cathepsin B at 3 h or 6 h, increase in tBid, reduction in mitochondrial cytochrome-c (Cyt-c) and increase in cytoplastic Cyt-c and active caspase-3 at 12-24 h of the late stage of pMCAO or OGD. CA-074Me or Clik148 also reduced cytosolic and mitochondrial tBid, increased mitochondrial Cyt-c and decreased cytoplastic Cyt-c and active caspase-3 at 6 h of the early stage of Bid activation. CA-074Me or Clik148 blocked the pMCAO-induced release of cathepsin B or L from the lysosomes into the cytoplasm and activation of caspase-3 in ischemic astrocytes at 12 h after ischemia. Concurrent inhibition of cathepsin B and cathepsin L provided better protection on the OGD-induced astrocytic apoptosis than obtained with separate use of each inhibitor. These results suggest that inhibition of the cysteine cathepsin B and cathepsin L activation in ischemic astrocytes contributes to neuroprotection via blocking the tBid-mitochondrial apoptotic signaling pathway.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Catepsina B
/
Isquemia Encefálica
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Astrócitos
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Fator de Indução de Apoptose
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Proteína Agonista de Morte Celular de Domínio Interatuante com BH3
/
Catepsina L
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Glia
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
China