Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (4): 1574-1585.doi: 10.4103/NRR.NRR-D-23-01953

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Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathway

Jie Jing1, 2, #, Shiling Chen1, #, Xuan Wu1 , Jingfei Yang1 , Xia Liu1 , Jiahui Wang1 , Jingyi Wang1 , Yunjie Li1 , Ping Zhang1, *, Zhouping Tang1, *   

  1. 1 Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China;  2 Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
  • Online:2026-04-15 Published:2025-07-28
  • Contact: Ping Zhang, MD, ppkitty0609@163.com; Zhouping Tang, PhD, ddjtzp@163.com.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China, Nos. 92148206, 82071330 (both to ZT); a grant from the Major Program of Hubei Province, No. 2023BAA005 (to ZT); a grant from the Key Research and Discovery Program of Hubei Province, No. 2021BCA109 (to ZT); and the Research Foundation of Tongji Hospital, No. 2022B37 (to PZ).

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Abstract: 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/threonineprotein 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.

Key words: 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