Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress
Neuroserpin, a secreted protein that belongs to the serpin superfamily of serine protease inhibitors, is highly expressed in the central nervous system and plays multiple roles in brain development and pathology. As a natural inhibitor of recombinant tissue plasminogen activator, neuroserpin inhibit...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Medknow Publications
2026-01-01
|
| Series: | Neural Regeneration Research |
| Subjects: | |
| Online Access: | https://journals.lww.com/10.4103/NRR.NRR-D-24-00044 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849734075488665600 |
|---|---|
| author | Yumei Liao Qinghua Zhang Qiaoyun Shi Peng Liu Peiyun Zhong Lingling Guo Zijian Huang Yinghui Peng Wei Liu Shiqing Zhang István Adorján Yumi Fukuzaki Eri Kawashita Xiao-Qi Zhang Nan Ma Xiaoshen Zhang Zoltán Molnár Lei Shi |
| author_facet | Yumei Liao Qinghua Zhang Qiaoyun Shi Peng Liu Peiyun Zhong Lingling Guo Zijian Huang Yinghui Peng Wei Liu Shiqing Zhang István Adorján Yumi Fukuzaki Eri Kawashita Xiao-Qi Zhang Nan Ma Xiaoshen Zhang Zoltán Molnár Lei Shi |
| author_sort | Yumei Liao |
| collection | DOAJ |
| description | Neuroserpin, a secreted protein that belongs to the serpin superfamily of serine protease inhibitors, is highly expressed in the central nervous system and plays multiple roles in brain development and pathology. As a natural inhibitor of recombinant tissue plasminogen activator, neuroserpin inhibits the increased activity of tissue plasminogen activator in ischemic conditions and extends the therapeutic windows of tissue plasminogen activator for brain ischemia. However, the neuroprotective mechanism of neuroserpin against ischemic stroke remains unclear. In this study, we used a mouse model of middle cerebral artery occlusion and oxygen-glucose deprivation/reperfusion-injured cortical neurons as in vivo and in vitro ischemia-reperfusion models, respectively. The models were used to investigate the neuroprotective effects of neuroserpin. Our findings revealed that endoplasmic reticulum stress was promptly triggered following ischemia, initially manifesting as the acute activation of endoplasmic reticulum stress transmembrane sensors and the suppression of protein synthesis, which was followed by a later apoptotic response. Notably, ischemic stroke markedly downregulated the expression of neuroserpin in cortical neurons. Exogenous neuroserpin reversed the activation of multiple endoplasmic reticulum stress signaling molecules, the reduction in protein synthesis, and the upregulation of apoptotic transcription factors. This led to a reduction in neuronal death induced by oxygen/glucose deprivation and reperfusion, as well as decreased cerebral infarction and neurological dysfunction in mice with middle cerebral artery occlusion. However, the neuroprotective effects of neuroserpin were markedly inhibited by endoplasmic reticulum stress activators thapsigargin and tunicamycin. Our findings demonstrate that neuroserpin exerts neuroprotective effects on ischemic stroke by suppressing endoplasmic reticulum stress. |
| format | Article |
| id | doaj-art-b12dc9f9fdc0478a8d70fecccae21e5a |
| institution | DOAJ |
| issn | 1673-5374 1876-7958 |
| language | English |
| publishDate | 2026-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj-art-b12dc9f9fdc0478a8d70fecccae21e5a2025-08-20T03:07:54ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53741876-79582026-01-0121133334510.4103/NRR.NRR-D-24-00044Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stressYumei LiaoQinghua ZhangQiaoyun ShiPeng LiuPeiyun ZhongLingling GuoZijian HuangYinghui PengWei LiuShiqing ZhangIstván AdorjánYumi FukuzakiEri KawashitaXiao-Qi ZhangNan MaXiaoshen ZhangZoltán MolnárLei ShiNeuroserpin, a secreted protein that belongs to the serpin superfamily of serine protease inhibitors, is highly expressed in the central nervous system and plays multiple roles in brain development and pathology. As a natural inhibitor of recombinant tissue plasminogen activator, neuroserpin inhibits the increased activity of tissue plasminogen activator in ischemic conditions and extends the therapeutic windows of tissue plasminogen activator for brain ischemia. However, the neuroprotective mechanism of neuroserpin against ischemic stroke remains unclear. In this study, we used a mouse model of middle cerebral artery occlusion and oxygen-glucose deprivation/reperfusion-injured cortical neurons as in vivo and in vitro ischemia-reperfusion models, respectively. The models were used to investigate the neuroprotective effects of neuroserpin. Our findings revealed that endoplasmic reticulum stress was promptly triggered following ischemia, initially manifesting as the acute activation of endoplasmic reticulum stress transmembrane sensors and the suppression of protein synthesis, which was followed by a later apoptotic response. Notably, ischemic stroke markedly downregulated the expression of neuroserpin in cortical neurons. Exogenous neuroserpin reversed the activation of multiple endoplasmic reticulum stress signaling molecules, the reduction in protein synthesis, and the upregulation of apoptotic transcription factors. This led to a reduction in neuronal death induced by oxygen/glucose deprivation and reperfusion, as well as decreased cerebral infarction and neurological dysfunction in mice with middle cerebral artery occlusion. However, the neuroprotective effects of neuroserpin were markedly inhibited by endoplasmic reticulum stress activators thapsigargin and tunicamycin. Our findings demonstrate that neuroserpin exerts neuroprotective effects on ischemic stroke by suppressing endoplasmic reticulum stress.https://journals.lww.com/10.4103/NRR.NRR-D-24-00044endoplasmic reticulum stressischemia-reperfusion injuryneuronneuronal apoptosisneuroprotectionneuroserpinprotein synthesissecretory proteinstroketranscriptomic analysis |
| spellingShingle | Yumei Liao Qinghua Zhang Qiaoyun Shi Peng Liu Peiyun Zhong Lingling Guo Zijian Huang Yinghui Peng Wei Liu Shiqing Zhang István Adorján Yumi Fukuzaki Eri Kawashita Xiao-Qi Zhang Nan Ma Xiaoshen Zhang Zoltán Molnár Lei Shi Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress Neural Regeneration Research endoplasmic reticulum stress ischemia-reperfusion injury neuron neuronal apoptosis neuroprotection neuroserpin protein synthesis secretory protein stroke transcriptomic analysis |
| title | Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress |
| title_full | Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress |
| title_fullStr | Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress |
| title_full_unstemmed | Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress |
| title_short | Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress |
| title_sort | neuroserpin alleviates cerebral ischemia reperfusion injury by suppressing ischemia induced endoplasmic reticulum stress |
| topic | endoplasmic reticulum stress ischemia-reperfusion injury neuron neuronal apoptosis neuroprotection neuroserpin protein synthesis secretory protein stroke transcriptomic analysis |
| url | https://journals.lww.com/10.4103/NRR.NRR-D-24-00044 |
| work_keys_str_mv | AT yumeiliao neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT qinghuazhang neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT qiaoyunshi neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT pengliu neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT peiyunzhong neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT linglingguo neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT zijianhuang neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT yinghuipeng neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT weiliu neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT shiqingzhang neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT istvanadorjan neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT yumifukuzaki neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT erikawashita neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT xiaoqizhang neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT nanma neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT xiaoshenzhang neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT zoltanmolnar neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress AT leishi neuroserpinalleviatescerebralischemiareperfusioninjurybysuppressingischemiainducedendoplasmicreticulumstress |