title: Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: Involvement of PARK2-dependent mitophagy.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Jingying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Zhejiang Provincial Key Laboratory of Medical Genetics; School of Life Sciences; Wenzhou Medical College; Wenzhou, China.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Tian
authors.initials: T
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Haijing
authors.initials: H
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Wenlu
authors.initials: W
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Hou
authors.affiliation: Zhejiang Provincial Key Laboratory of Medical Genetics; School of Life Sciences; Wenzhou Medical College; Wenzhou, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.affiliation: Zhejiang Provincial Key Laboratory of Medical Genetics; School of Life Sciences; Wenzhou Medical College; Wenzhou, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pharmacy; the Second Affiliated Hospital; School of Medicine; Zhejiang University; Hangzhou, China.
authors.forename: Haibing
authors.initials: H
authors.lastname: Dai
authors.affiliation: 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.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Medical Genetics; Central South University; Changsha, China.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D051379:Mice; D063306:Mitophagy / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010100:Oxygen / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology / Q000627:therapeutic use*; D014415:Tunicamycin / Q000494:pharmacology / Q000627:therapeutic use*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D014415:Tunicamycin; D019284:Thapsigargin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D005947:Glucose; D010100:Oxygen
keywords: PARK2; cerebral ischemia; endoplasmic reticulum stress; mitophagy; neuroprotection