MST1 Suppression Reduces Early Brain Injury by Inhibiting the NF-κB/MMP-9 Pathway after Subarachnoid Hemorrhage in Mice

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.

XMU-MP-1 induces growth arrest in a model human mini-organ and antagonises cell cycle-dependent paclitaxel cytotoxicity

“…However, supporting KINOMEscan profiling data within this same study reported that XMU-MP-1 has a strong affinity to inhibit an additional 21 kinases [ 8 ]. Despite this, follow-up studies have since claimed to have successfully utilised XMU-MP-1 to specifically target Hippo signalling, highlighting protective applications against early brain injury [ 9 ] and cardiac pressure overload [ 10 ].…”

The emerging role of Hippo signaling in neurodegeneration

“…Hence, this Src‐MST1‐IκBα signaling forms the critical player in microglial activation and ultimately neuronal death (Zhao et al, ). Hyperactivation of Hippo signaling has also been associated with several other stroke‐like conditions including traumatic brain injury (TBI) (Liang et al, ), subarachnoid hemorrhage (SAH) (Qu et al, ), and intracerebral hemorrhage (ICH) (Zhang et al, ).…”

“…Furthermore, it has been demonstrated that stroke‐induced brain injury mitigates upon specific deletion of microglial MST , exhibiting the therapeutic potential of MST in stroke and other microglial activation‐mediated neurological disorders (Zhao et al, ). In SAH mouse model, intraperitoneal injection of the MST1 inhibitor, Xmu‐mp‐1, and intracerebroventricular injection of MST1 shRNA reduced neuroinflammation, improved blood–brain barrier (BBB) disruption, brain edema, and white matter injury by inhibiting the NF‐ κ B/MMP‐9 pathway (Qu et al, ). Inhibition of MST1 via drug Xmu‐mp‐1 or via MST1 shRNA in ICH‐established SD rat model was also found to have decreased neuronal death.In addition, MST1 deficiency also repaired BBB damage, reduced brain edema, and improved neurobehavioral impairments, thereby highlighting MST1 as a suitable target for stroke therapeutics (Zhang et al, ).…”

“…Hyperactivation of Hippo signaling has also been associated with several other stroke-like conditions including traumatic brain injury (TBI) (Liang et al, 2017), subarachnoid hemorrhage (SAH) (Qu et al, 2018), and intracerebral hemorrhage (ICH) .…”

<p>The Clinical Effect of Electroconvulsive Therapy and Its Relationship with Serum Levels of MMP-9 and CXCL12 in Patients with Mania</p>

“…[16][17][18] Currently, it has been shown that MMP-9 plays a very important two-way role in the central nervous system, and that can be either the intermediate between pathological pathways or the central player in the regeneration of the central nervous system. 19,20 MMP-9 can open the blood-brain barrier and increase its permeability. It has previously been proposed that ECT increases bloodbrain barriers permeability in cerebrovascular.…”