Inhibition of cysteine cathepsin B and L activation in astrocytes contributes to neuroprotection against cerebral ischemia via blocking the tBid-mitochondrial apoptotic signaling pathway

• Published in: Glia Vol. 62; no. 6; pp. 855 - 880
• Main Authors: Xu, Min, Yang, Lei, Rong, Jia-Guo, Ni, Yong, Gu, Wei-Wei, Luo, Yu, Ishidoh, Kazumi, Katunuma, Nobuhiko, Li, Zhong-Sheng, Zhang, Hui-Ling
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.06.2014; Wiley Subscription Services, Inc
• Subjects: Animals; apoptosis; Apoptosis Inducing Factor - antagonists & inhibitors; Apoptosis Inducing Factor - metabolism; astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; BH3 Interacting Domain Death Agonist Protein - antagonists & inhibitors; BH3 Interacting Domain Death Agonist Protein - metabolism; Brain Ischemia - metabolism; Brain Ischemia - prevention & control; Cathepsin B - antagonists & inhibitors; Cathepsin B - metabolism; Cathepsin L - antagonists & inhibitors; Cathepsin L - metabolism; cathepsins; Cells, Cultured; cerebral ischemia; Cysteine - antagonists & inhibitors; Cysteine - metabolism; Epoxy Compounds - pharmacology; Epoxy Compounds - therapeutic use; Ischemia; Male; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Rats, Sprague-Dawley; tBid; apoptosis; astrocytes; tBid; cathepsins; cerebral ischemia
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22645

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. GLIA 2014;62:855–880 Main points CA‐074Me or Clik148 produces neuroprotection against ischemia. CA‐074Me or Clik148 protects ischemic astrocytes. Cathepsin B and L participate in the ischemic astrocytic injury via activating the tBid‐mitochondrial apoptotic signaling pathway.