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

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.

• Authors: Min Xu, Lei Yang, Jia-Guo Rong, Yong Ni, Wei-Wei Gu, Yu Luo, Kazumi Ishidoh, Nobuhiko Katunuma, Zhong-Sheng Li, Hui-Ling Zhang
• Journal: Glia (Glia) Vol. 62 Issue 6 Pg. 855-80 (Jun 2014) ISSN: 1098-1136 [Electronic] United States
• PMID: 24616078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Wiley Periodicals, Inc.

Chemical References

• Apoptosis Inducing Factor
• BH3 Interacting Domain Death Agonist Protein
• CLIK 148
• Epoxy Compounds
• Neuroprotective Agents
• Pyridines
• Cathepsin B
• Ctsb protein, rat
• Cathepsin L
• Ctsl protein, rat
• Cysteine

Topics

• Animals
• Apoptosis Inducing Factor (antagonists & inhibitors, metabolism)
• Astrocytes (drug effects, metabolism)
• BH3 Interacting Domain Death Agonist Protein (antagonists & inhibitors, metabolism)
• Brain Ischemia (metabolism, prevention & control)
• Cathepsin B (antagonists & inhibitors, metabolism)
• Cathepsin L (antagonists & inhibitors, metabolism)
• Cells, Cultured
• Cysteine (antagonists & inhibitors, metabolism)
• Epoxy Compounds (pharmacology, therapeutic use)
• Male
• Neuroprotective Agents (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley