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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. 2014 Jun; 62(6):855-80.GLIA

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+Show Affiliations

Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24616078

Citation

Xu, Min, et al. "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, vol. 62, no. 6, 2014, pp. 855-80.
Xu M, Yang L, Rong JG, et al. 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. 2014;62(6):855-80.
Xu, M., Yang, L., Rong, J. G., Ni, Y., Gu, W. W., Luo, Y., Ishidoh, K., Katunuma, N., Li, Z. S., & Zhang, H. L. (2014). 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. https://doi.org/10.1002/glia.22645
Xu M, et al. 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. 2014;62(6):855-80. PubMed PMID: 24616078.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of cysteine cathepsin B and L activation in astrocytes contributes to neuroprotection against cerebral ischemia via blocking the tBid-mitochondrial apoptotic signaling pathway. AU - Xu,Min, AU - Yang,Lei, AU - Rong,Jia-Guo, AU - Ni,Yong, AU - Gu,Wei-Wei, AU - Luo,Yu, AU - Ishidoh,Kazumi, AU - Katunuma,Nobuhiko, AU - Li,Zhong-Sheng, AU - Zhang,Hui-Ling, Y1 - 2014/02/24/ PY - 2013/07/31/received PY - 2014/01/15/revised PY - 2014/01/27/accepted PY - 2014/3/12/entrez PY - 2014/3/13/pubmed PY - 2014/12/17/medline KW - apoptosis KW - astrocytes KW - cathepsins KW - cerebral ischemia KW - tBid SP - 855 EP - 80 JF - Glia JO - Glia VL - 62 IS - 6 N2 - 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. SN - 1098-1136 UR - https://www.unboundmedicine.com/medline/citation/24616078/Inhibition_of_cysteine_cathepsin_B_and_L_activation_in_astrocytes_contributes_to_neuroprotection_against_cerebral_ischemia_via_blocking_the_tBid_mitochondrial_apoptotic_signaling_pathway_ L2 - https://doi.org/10.1002/glia.22645 DB - PRIME DP - Unbound Medicine ER -