Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathway
Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage. However, during minimally invasive surgery, recombinant tissue plasminogen activator may come into contact with brain tissue. Therefore, a thorough asse...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2026-04-01
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| Series: | Neural Regeneration Research |
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| Online Access: | https://journals.lww.com/10.4103/NRR.NRR-D-23-01953 |
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| author | Jie Jing Shiling Chen Xuan Wu Jingfei Yang Xia Liu Jiahui Wang Jingyi Wang Yunjie Li Ping Zhang Zhouping Tang |
| author_facet | Jie Jing Shiling Chen Xuan Wu Jingfei Yang Xia Liu Jiahui Wang Jingyi Wang Yunjie Li Ping Zhang Zhouping Tang |
| author_sort | Jie Jing |
| collection | DOAJ |
| description | Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage. However, during minimally invasive surgery, recombinant tissue plasminogen activator may come into contact with brain tissue. Therefore, a thorough assessment of its safety is required. In this study, we established a mouse model of intracerebral hemorrhage induced by type VII collagenase. We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage, reduced pathological damage, and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma. In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin, the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis, autophagy, and endoplasmic reticulum stress. Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons. Moreover, the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis, autophagy, and endoplasmic reticulum stress. Furthermore, to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects, various inhibitors were used to target distinct domains. It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway. These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage, possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway. |
| format | Article |
| id | doaj-art-e8cecc07bad7498ab222bab5ab69f56b |
| institution | Kabale University |
| issn | 1673-5374 1876-7958 |
| language | English |
| publishDate | 2026-04-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj-art-e8cecc07bad7498ab222bab5ab69f56b2025-08-20T03:31:30ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53741876-79582026-04-012141574158510.4103/NRR.NRR-D-23-01953Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathwayJie JingShiling ChenXuan WuJingfei YangXia LiuJiahui WangJingyi WangYunjie LiPing ZhangZhouping TangRecombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage. However, during minimally invasive surgery, recombinant tissue plasminogen activator may come into contact with brain tissue. Therefore, a thorough assessment of its safety is required. In this study, we established a mouse model of intracerebral hemorrhage induced by type VII collagenase. We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage, reduced pathological damage, and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma. In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin, the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis, autophagy, and endoplasmic reticulum stress. Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons. Moreover, the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis, autophagy, and endoplasmic reticulum stress. Furthermore, to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects, various inhibitors were used to target distinct domains. It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway. These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage, possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.https://journals.lww.com/10.4103/NRR.NRR-D-23-01953apoptosisautophagyendoplasmic reticulum stressepidermal growth factorintracerebral hemorrhagemammalian target of rapamycinminimally invasive surgeryphosphoinositide 3-kinaserac-alpha serine/threonine-protein kinaserecombinant tissue plasminogen activator |
| spellingShingle | Jie Jing Shiling Chen Xuan Wu Jingfei Yang Xia Liu Jiahui Wang Jingyi Wang Yunjie Li Ping Zhang Zhouping Tang Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathway Neural Regeneration Research apoptosis autophagy endoplasmic reticulum stress epidermal growth factor intracerebral hemorrhage mammalian target of rapamycin minimally invasive surgery phosphoinositide 3-kinase rac-alpha serine/threonine-protein kinase recombinant tissue plasminogen activator |
| title | Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathway |
| title_full | Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathway |
| title_fullStr | Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathway |
| title_full_unstemmed | Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathway |
| title_short | Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathway |
| title_sort | recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the pi3k akt mtor pathway |
| topic | apoptosis autophagy endoplasmic reticulum stress epidermal growth factor intracerebral hemorrhage mammalian target of rapamycin minimally invasive surgery phosphoinositide 3-kinase rac-alpha serine/threonine-protein kinase recombinant tissue plasminogen activator |
| url | https://journals.lww.com/10.4103/NRR.NRR-D-23-01953 |
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