Abstract
Neuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.
Highlights
Subarachnoid hemorrhage (SAH) is a major cause of morbidity and mortality in neurosurgery practice[1,2]
We have demonstrated the following (Fig. 8C): (1) the expression of TRAF3 was upregulated after SAH both in mouse cortex and in primary cortical neurons; (2) after silencing TRAF3 gene by siRNA, the activation of TAK1/Mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathway were inhibited; (3) the downregulation of TRAF3 was sufficient to reduce neuronal apoptosis both in vivo and in vitro following SAH; (4) the downregulation of TRAF3 alleviated the neurological deficits of SAH mice as demonstrated by the reduction in the Modified Garcia scores; (5) the TRAF3 expression was upregulated in neurons in patients who had experienced SAH
Considering the above findings, TRAF3 may serve as an ideal therapeutic target in SAHinduced Early brain injury (EBI)
Summary
Subarachnoid hemorrhage (SAH) is a major cause of morbidity and mortality in neurosurgery practice[1,2]. Brain injury (EBI) is regarded as the main factor for poor prognosis after SAH3,4. Neuronal apoptosis has been demonstrated to have a vital role in EBI5,6. Mitogen-activated protein kinases (MAPKs) involving c-Jun-N-terminal kinases (JNK), P38, and nuclear factorkappa B (NF-κB) signaling pathways have been demonstrated to have an important role in the development of EBI after SAH9–11. They have been shown to aggravate brain damage by initiating apoptotic pathways[11]. Therapies that can regulate both MAPKs and NF-κB pathways are superior to single-target agents
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