White Matter Injury in Early Brain Injury after Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) is a major cause of high morbidity, disability, and mortality in the field of neurovascular disease. Most previous SAH studies have focused on improving cerebral blood flow, reducing cerebral vasospasm, reducing neuronal calcium overload, and other treatments. While these studies showed exciting findings in basic science, therapeutic strategies based on the findings have not significantly improved neurological outcomes in patients with SAH. Currently, the only drug proven to effectively reduce the neurological defects of SAH patients is nimodipine. Current advances in imaging technologies in the field of stroke have confirmed that white matter injury (WMI) plays an important role in the prognosis of types of stroke, and suggests that WMI protection is essential for functional recovery and poststroke rehabilitation. However, WMI injury in relation to SAH has remained obscure until recently. An increasing number of studies suggest that the current limitations for SAH treatment are probably linked to overlooked WMI in previous studies that focused only on neurons and gray matter. In this review, we discuss the biology and functions of white matter in the normal brain, and discuss the potential pathophysiology and mechanisms of early brain injury after SAH. Our review demonstrates that WMI encompasses multiple substrates, and, therefore, more than one pharmacological approach is necessary to preserve WMI and prevent neurobehavioral impairment after SAH. Strategies targeting both neuronal injury and WMI may potentially provide a novel future for SAH knowledge and treatment.

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GPR18 Agonist Resolvin D2 Reduces the Early Brain Injury in A Rat Model of Subarachnoid Hemorrhage by Multi-Mechanisms of Protection

10.21203/rs.3.rs-398477/v1 ◽

2021 ◽

Author(s):

Tongyu Zhang ◽

Gang Zuo ◽

Hongqi Zhang

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

White Matter ◽

Western Blot ◽

Rat Model ◽

Time Course ◽

Early Brain Injury ◽

Brain Regions ◽

White Matter Injury ◽

Tnf Α

Abstract Background Early brain injury (EBI) is the early phase of secondary complications resulted in poor prognosis of subarachnoid hemorrhage (SAH). GPR18 is a G protein-coupled receptor which has been reported for neuroprotection in ischemia. In this study, we aimed to use resolvin D2 (RvD2) as an agonist to investigate the roles of GPR18 in different brain regions during EBI. Methods Location and time course of GPR18 after SAH were measured with immunofluorescence and western blot in endovascular perforation rat model. RvD2 was given one hour intranasally post-SAH, and SAH grades, neurobehavior and brain water content tests were performed after 24 hours. TUNEL and DHE staining were measured 24 hours post-SAH in cortex. Immunofluorescence, western blot and immunohistochemistry of proteins related to EBI in different brain regions were also performed. Results We found GPR18 mainly located in meninges, hypothalamus, cortex and white matter. And GPR18 expression increased in meninges and hypothalamus after EBI, however, it decreased in cortex and white matter. RvD2 could improve neurological scores and brain edema. Mast cell degranulation was attenuated, Chymase and Typtase expression decreased after RvD2 administration in meninges. RvD2 attenuated inflammation with increase of POMC, IL-10 and decrease of NPY, TNF-α in hypothalamus. In cortex, RvD2 alleviated oxidative stress and apoptosis, protected blood-brain barrier. RvD2 also ameliorated white matter injury by MBP elevation and APP depression. Conclusions Current results emphasized the importance of GPR18 in the whole brain during EBI. Upregulation of GPR18 with RvD2 may improve neurological functions with multi-mechanisms in different brain regions.

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

Behavioural Neurology ◽

10.1155/2018/6470957 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Jie Qu ◽

Hengli Zhao ◽

Qiang Li ◽

Pengyu Pan ◽

Kang Ma ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

White Matter ◽

Early Brain Injury ◽

White Matter Injury ◽

Neurological Deficits ◽

Tunel Staining ◽

Blue Dye ◽

Junction Protein ◽

Cord Injury

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.

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High Mobility Group Box Protein 1 (HMGB1) and White Matter Injury following Traumatic Brain Injury (TBI): perspectives on mechanisms and therapeutic strategies

Neural Regeneration Research ◽

10.4103/1673-5374.332135 ◽

2022 ◽

Vol 17 (8) ◽

pp. 0

Author(s):

Ronak Ved ◽

Susruta Manivannan ◽

Imogen Tasker ◽

Malik Zaben

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

White Matter ◽

High Mobility ◽

Therapeutic Strategies ◽

High Mobility Group ◽

White Matter Injury

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Thrombin Inhibition by Argatroban Ameliorates Early Brain Injury and Improves Neurological Outcomes After Experimental Subarachnoid Hemorrhage in Rats

Stroke ◽

10.1161/strokeaha.108.531699 ◽

2009 ◽

Vol 40 (4) ◽

pp. 1530-1532 ◽

Cited By ~ 40

Author(s):

Takashi Sugawara ◽

Vikram Jadhav ◽

Robert Ayer ◽

Wanqiu Chen ◽

Hidenori Suzuki ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Early Brain Injury ◽

Neurological Outcomes ◽

Thrombin Inhibition ◽

Experimental Subarachnoid Hemorrhage

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Clinical Trials in Cardiac Arrest and Subarachnoid Hemorrhage: Lessons from the Past and Ideas for the Future

Stroke Research and Treatment ◽

10.1155/2013/263974 ◽

2013 ◽

Vol 2013 ◽

pp. 1-42

Author(s):

Jennifer A. Frontera

Keyword(s):

Clinical Trials ◽

Cardiac Arrest ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Randomized Clinical Trials ◽

Early Brain Injury ◽

Aneurysm Rupture ◽

Neurological Outcomes ◽

Injury Research ◽

The Brain

Introduction. Elevated intracranial pressure that occurs at the time of cerebral aneurysm rupture can lead to inadequate cerebral blood flow, which may mimic the brain injury cascade that occurs after cardiac arrest. Insights from clinical trials in cardiac arrest may provide direction for future early brain injury research after subarachnoid hemorrhage (SAH).Methods. A search of PubMed from 1980 to 2012 and clinicaltrials.gov was conducted to identify published and ongoing randomized clinical trials in aneurysmal SAH and cardiac arrest patients. Only English, adult, human studies with primary or secondary mortality or neurological outcomes were included.Results. A total of 142 trials (82 SAH, 60 cardiac arrest) met the review criteria (103 published, 39 ongoing). The majority of both published and ongoing SAH trials focus on delayed secondary insults after SAH (70%), while 100% of cardiac arrest trials tested interventions within the first few hours of ictus. No SAH trials addressing treatment of early brain injury were identified. Twenty-nine percent of SAH and 13% of cardiac arrest trials showed outcome benefit, though there is no overlap mechanistically.Conclusions. Clinical trials in SAH assessing acute brain injury are warranted and successful interventions identified by the cardiac arrest literature may be reasonable targets of the study.

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TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways

Cell Death and Disease ◽

10.1038/s41419-020-03278-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yan Zhou ◽

Tao Tao ◽

Guangjie Liu ◽

Xuan Gao ◽

Yongyue Gao ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Therapeutic Target ◽

Cortical Neurons ◽

Neuronal Apoptosis ◽

Early Brain Injury ◽

Neurological Deficits ◽

Human Brain Tissue

AbstractNeuronal 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.

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