Abstract
Background Mammalian sterile 20-like kinase 1 (MST1), the key component of the Hippo-YAP pathway, exhibits an important role in the pathophysiological process of various neurological disorders, including ischemic stroke and spinal cord injury. However, during subarachnoid hemorrhage, the involvement of MST1 in the pathophysiology of early brain injury remains unknown. Methods We employed intravascular filament perforation to establish the subarachnoid hemorrhage (SAH) mouse model. The MST1 inhibitor XMU-MP-1 was intraperitoneally injected at 1 h after SAH, followed by daily injections. MST1 in vivo knockdown was performed 3 weeks prior to SAH via intracerebroventricular injection of adeno-associated virus (AAV) packaged with MST1 shRNA. The SAH grade, behavioral deficits, TUNEL staining, Evans blue dye extravasation and fluorescence, brain water content, protein and cytokine expressions by Western blotting, immunofluorescence, and proteome cytokine array were evaluated. Results Following SAH, the phosphorylation level of MST1 was upregulated at 12 h, with a peak at 72 h after SAH. It was colocalized with the microglial marker Iba1. Both XMU-MP-1 and MST1 shRNA alleviated the neurological deficits, blood-brain barrier (BBB) disruption, brain edema, neuroinflammation, and white matter injury, which were induced by SAH in association with nuclear factor- (NF-) κB p65 and matrix metallopeptidase-9 (MMP-9) activation and downregulated endothelial junction protein expression. Conclusions The current findings indicate that MST1 participates in SAH-induced BBB disruption and white matter fiber damage via the downstream NF-κB-MMP-9 signaling pathway. Therefore, MST1 antagonists may serve as a novel therapeutic target to prevent early brain injury in SAH patients.
Highlights
Subarachnoid hemorrhage (SAH) is identified as a subtype of hemorrhage stroke; it is mainly caused by a ruptured aneurysm, with high mortality and morbidity worldwide [1]
The subarachnoid hemorrhage (SAH) grading score results showed that there were no significant differences among the experimental SAH groups at 24 h or 72 h (Figure 3). 4 mice (2 in the SAH group, 1 in the 3 mg/kg group, and 1 in the 10 mg/kg group) with a score < 8 as well as no obvious neurological deficits were excluded from further analysis, and 8 mice (1 in the SAH group, 2 in the vehicle group, 1 in the 3 mg/kg group, 2 in the 10 mg/kg group, and 2 in the 15 mg/kg group) that underwent SAH died due to severe hemorrhagic volume within 24 h of SAH
The result of the SAH grading score showed that there was no significant difference among these experimental SAH (Figure 3(c)). 3 mice (2 in the SAH group and 1 in the shRNA group) with a score < 8 as well as no obvious neurological deficits were excluded from further analysis
Summary
Subarachnoid hemorrhage (SAH) is identified as a subtype of hemorrhage stroke; it is mainly caused by a ruptured aneurysm, with high mortality and morbidity worldwide [1]. Recent studies have indicated the pivotal role of the vascular neural network in the pathophysiological process of early brain injury after SAH [2]. Mammalian sterile 20-like kinase 1 (MST1), the key component of the Hippo-YAP pathway, exhibits an important role in the pathophysiological process of various neurological disorders, including ischemic stroke and spinal cord injury. Following SAH, the phosphorylation level of MST1 was upregulated at 12 h, with a peak at 72 h after SAH It was colocalized with the microglial marker Iba. It was colocalized with the microglial marker Iba1 Both XMU-MP-1 and MST1 shRNA alleviated the neurological deficits, blood-brain barrier (BBB) disruption, brain edema, neuroinflammation, and white matter injury, which were induced by SAH in association with nuclear factor- (NF-) κB p65 and matrix metallopeptidase-9 (MMP-9) activation and downregulated endothelial junction protein expression. MST1 antagonists may serve as a novel therapeutic target to prevent early brain injury in SAH patients
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