期刊
BRAIN RESEARCH BULLETIN
卷 120, 期 -, 页码 97-105出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.brainresbull.2015.11.007
关键词
CA074-me; Cathepsin-B; Lysosomal membrane permeabilization; Ischemia/reperfusion injury; Receptor-interacting protein 3; Heat shock protein 70
资金
- National Natural Science Foundation of China [81271272, 81100877]
- PhD Programs Foundation of the Ministry of Education of China [20113420120003]
- Key Research Program for Traditional Chinese Medicine of Zhejiang Province [2013ZZ010]
- Zhejiang University Experiment Research Foundation [SYB201410]
- Natural Science foundation of Zhejiang Province [LY13H090004]
Many studies have demonstrated the key role of lysosomes in ischemic cell death in the brain and have led to the lysosomocentric hypothesis. In this hypothesis, the release of cathepsin-B due to a change of lysosomal membrane permeabilization (LMP) or rupture is critical, and this can be prevented by its inhibitors CA074 and CA074-me. However, the role of CA074-me in neuronal death and its effect on the change of lysosomal membrane integrity after global cerebral ischemia/reperfusion (I/R) injury is not clear, so we investigated this here. Rat hippocampal CA1 neuronal death was evaluated after 20-min global cerebral I/R injury. CA074-me (1 mu g, 10 mu g) were given intracerebroventricularly 1 h before ischemia or 1 h post reperfusion. The changes of heat shock protein 70 (Hsp70), cathepsin-B, lysosomal-associated membrane protein I (LAMP-1), receptor-interacting protein 3 (RIP3), and the change of lysosomal pH were evaluated respectively. Hippocampal CM neuronal programmed necrosis induced by global cerebral I/R injury was prevented by CA074-me both pre-treatment and post-treatment. Diffuse cytoplasmic cathepsin-B and LAMP-1 immunostaining synchronized with the pyknotic nuclear changes 2 days post reperfusion, and a rise of lysosomal pH with the leakage of DND-153, a dye of lysosomes, after oxygen-glucose deprivation (OGD) was detected. Both of these changes demonstrated the rupture of lysosomal membrane and the leakage of cathepsin-B, and this was strongly inhibited by CA074-me pre-treatment. The overexpression and nuclear translocation of RIP3 and the reduction of NAD* level after I/R injury were also inhibited, while the upregulation of Hsp70 was strengthened by CA074-me pre-treatment. Delayed fulminant leakage of cathepsin-B due to lysosomal rupture is a critical harmful factor in neuronal programmed necrosis induced by 20-min global I/R injury. In addition to being an inhibitor of cathepsin-B, CA074-me may have an indirect neuroprotective effect by maintaining lysosomal membrane integrity and protecting against lysosomal rupture. (C) 2015 Elsevier Inc. All rights reserved.
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