2. Academic Validation
  3. Tyrosine kinase Fyn promotes apoptosis after intracerebral hemorrhage in rats by activating Drp1 signaling

Tyrosine kinase Fyn promotes apoptosis after intracerebral hemorrhage in rats by activating Drp1 signaling

  • J Mol Med (Berl). 2021 Mar;99(3):359-371. doi: 10.1007/s00109-020-02022-6.
Li Zhang 1 2 3 4,  Lu Wang 1 2 3 4,  Han Xiao 1 2 3 4,  Hui Gan 1 2 3 4,  Hui Chen 1 2 3 4,  Shuyue Zheng 1 2 3 4,  Dan Jian 1 2 3 4,  Xuan Zhai 5 6 7 8,  Ning Jiang 9,  Zhao Jing 9,  Ping Liang 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 2 Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People's Republic of China.
  • 3 National Clinical Research Center for Child Health and Disorders, Chongqing, People's Republic of China.
  • 4 China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing, People's Republic of China.
  • 5 Department of Neurosurgery, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China. zhaixuan@163.com.
  • 6 Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People's Republic of China. zhaixuan@163.com.
  • 7 National Clinical Research Center for Child Health and Disorders, Chongqing, People's Republic of China. zhaixuan@163.com.
  • 8 China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing, People's Republic of China. zhaixuan@163.com.
  • 9 Institute of Neuroscience, School of Basic Medicine, Chongqing Medical University, Chongqing, 400010, People's Republic of China.
PMID: 33409551 DOI: 10.1007/s00109-020-02022-6
Abstract

Tyrosine kinase Fyn is a member of the Src kinase family, which is involved in neuroinflammation, Apoptosis, and oxidative stress. Its role in intracerebral hemorrhage (ICH) is not fully understood. In this study, we found that Fyn was significantly elevated in human brain tissue after ICH. Accordingly, we investigated the role of Fyn in a rat ICH model, which was constructed by injecting blood into the right basal ganglia. In this model, Fyn expression was significantly upregulated in brain tissue adjacent to the hematoma. SiRNA-induced Fyn knockdown was neuroprotective for secondary cerebral damage, as demonstrated by reduced brain edema, suppression of the modified neurological severity score, and mitigation of blood-brain barrier permeability and neuronal damage. Fyn downregulation reduced Apoptosis following ICH, as indicated by downregulation of apoptosis-related proteins AIF, Cyt.c, Caspase 3, and Bax; upregulation of anti-apoptosis-related protein Bcl-2; and decreased tunnel staining. Mdivi-1, a Drp1 inhibitor, reversed Fyn overexpression induced pro-apoptosis. However, Fyn did not significantly affect inflammation-related proteins NF-κB, TNF-α, Caspase 1, MPO, IL-1β, or IL-18 after ICH. Fyn activated Drp1 signaling by phosphorylating Drp1 at serine 616, which increased Apoptosis after ICH in rats. This study clarifies the relationship between Fyn, Apoptosis, and inflammation following ICH and provides a new strategy for exploring the prevention and treatment of ICH. KEY MESSAGES: ICH induced an increase in Fyn expression in human and rat cerebral tissues. Knockdown of Fyn prevented cerebral damage following ICH. Inhibition of Fyn had no significant effects on inflammatory responses. However, the downregulation of Fyn exerted neuroprotective effects on Apoptosis. Fyn perturbed ICH-induced cell Apoptosis by interacting with and phosphorylating (Ser616) Drp1 in a rat ICH model.

Keywords

Apoptosis; Drp1; Inflammatory; Intracerebral hemorrhage; Tyrosine kinase Fyn.

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