PMID- 25126734 OWN - NLM STAT- MEDLINE DCOM- 20150519 LR - 20211021 IS - 1554-8635 (Electronic) IS - 1554-8627 (Print) IS - 1554-8627 (Linking) VI - 10 IP - 10 DP - 2014 Oct 1 TI - Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: Involvement of PARK2-dependent mitophagy. PG - 1801-13 LID - 10.4161/auto.32136 [doi] AB - Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation. FAU - Zhang, Xiangnan AU - Zhang X AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China; Collaborative Innovation Center for Infectious Diseases; Zhejiang University; Hangzhou, China. FAU - Yuan, Yang AU - Yuan Y AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China. FAU - Jiang, Lei AU - Jiang L AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China. FAU - Zhang, Jingying AU - Zhang J AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China. FAU - Gao, Jieqiong AU - Gao J AD - Zhejiang Provincial Key Laboratory of Medical Genetics; School of Life Sciences; Wenzhou Medical College; Wenzhou, China. FAU - Shen, Zhe AU - Shen Z AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China. FAU - Zheng, Yanrong AU - Zheng Y AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China. FAU - Deng, Tian AU - Deng T AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China. FAU - Yan, Haijing AU - Yan H AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China. FAU - Li, Wenlu AU - Li W AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China; Department of Pharmacy; the Second Affiliated Hospital; School of Medicine; Zhejiang University; Hangzhou, China. FAU - Hou, Wei-Wei AU - Hou WW AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China. FAU - Lu, Jianxin AU - Lu J AD - Zhejiang Provincial Key Laboratory of Medical Genetics; School of Life Sciences; Wenzhou Medical College; Wenzhou, China. FAU - Shen, Yao AU - Shen Y AD - Zhejiang Provincial Key Laboratory of Medical Genetics; School of Life Sciences; Wenzhou Medical College; Wenzhou, China. FAU - Dai, Haibing AU - Dai H AD - Department of Pharmacy; the Second Affiliated Hospital; School of Medicine; Zhejiang University; Hangzhou, China. FAU - Hu, Wei-Wei AU - Hu WW AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China; Collaborative Innovation Center for Infectious Diseases; Zhejiang University; Hangzhou, China. FAU - Zhang, Zhuohua AU - Zhang Z AD - State Key Laboratory of Medical Genetics; Central South University; Changsha, China. FAU - Chen, Zhong AU - Chen Z AD - Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China; Collaborative Innovation Center for Infectious Diseases; Zhejiang University; Hangzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140805 PL - United States TA - Autophagy JT - Autophagy JID - 101265188 RN - 0 (Neuroprotective Agents) RN - 11089-65-9 (Tunicamycin) RN - 67526-95-8 (Thapsigargin) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.3.2.27 (parkin protein) RN - IY9XDZ35W2 (Glucose) RN - S88TT14065 (Oxygen) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Brain Ischemia/*drug therapy/pathology MH - *Endoplasmic Reticulum Stress/drug effects MH - Glucose/deficiency MH - Mice MH - *Mitophagy/drug effects MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Oxygen/metabolism MH - Reperfusion Injury/drug therapy MH - Signal Transduction/drug effects MH - Thapsigargin/pharmacology/*therapeutic use MH - Tunicamycin/pharmacology/*therapeutic use MH - Ubiquitin-Protein Ligases/*metabolism PMC - PMC4198364 OTO - NOTNLM OT - PARK2 OT - cerebral ischemia OT - endoplasmic reticulum stress OT - mitophagy OT - neuroprotection EDAT- 2014/08/16 06:00 MHDA- 2015/05/20 06:00 PMCR- 2015/10/01 CRDT- 2014/08/16 06:00 PHST- 2014/08/16 06:00 [entrez] PHST- 2014/08/16 06:00 [pubmed] PHST- 2015/05/20 06:00 [medline] PHST- 2015/10/01 00:00 [pmc-release] AID - 32136 [pii] AID - 2013AUTO0535R2 [pii] AID - 10.4161/auto.32136 [doi] PST - ppublish SO - Autophagy. 2014 Oct 1;10(10):1801-13. doi: 10.4161/auto.32136. Epub 2014 Aug 5.