title: 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.affiliation: Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Rong
authors.forename: Yong
authors.initials: Y
authors.lastname: Ni
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Gu
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ishidoh
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Katunuma
authors.forename: Zhong-Sheng
authors.initials: ZS
authors.lastname: Li
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Zhang
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D003545:Cysteine / Q000037:antagonists & inhibitors / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; C402823:CLIK 148; D004852:Epoxy Compounds; D018696:Neuroprotective Agents; D011725:Pyridines; D002401:Cathepsin B; C533916:Ctsb protein, rat; D056668:Cathepsin L; C534280:Ctsl protein, rat; D003545:Cysteine
keywords: apoptosis; astrocytes; cathepsins; cerebral ischemia; tBid