Inflammatory Pathways Following Subarachnoid Hemorrhage

Khey, Kevin M. W.; Huard, Alec; Mahmoud, Sherif Hanafy

doi:10.1007/s10571-019-00767-4

Cited by 48 publications

(37 citation statements)

References 226 publications

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“…Neuroinflammation, which is mediated by the activation of local microglia and recruitment of circulating immune cells such as neutrophils and macrophages, is one of the key drivers of secondary injury following SAH [42]. Previous studies including ours indicated that suppressing neuroinflammation confers a significant improvement in neurological outcome after SAH [27,41,43].…”

Section: Discussionmentioning

confidence: 62%

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

Peng

Zhuang

Ying

et al. 2020

J Neuroinflammation

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Background: Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. Methods: A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. Results: STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust antiinflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro.

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Section: Discussionmentioning

confidence: 62%

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

Peng

Zhuang

Ying

et al. 2020

J Neuroinflammation

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“…The progression of aSAH is individualized and rapid, so accurate risk stratification and prognosis prediction is challenging ( 4 ). A growing body of research has found that neuroinflammation and immune disorders after aSAH may play an important role in both early brain injury (EBI) and delayed neurological injury ( 5 ). Neutrophils and lymphocytes are vital inflammatory cells and participate in many pathogenic processes ( 6 ), such as endothelial injury, blood–brain barrier (BBB) destruction, microcirculation disturbance, and vasospasm ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of the Blood Neutrophil-to-Lymphocyte Ratio in Aneurysmal Subarachnoid Hemorrhage

et al. 2021

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Aneurysmal subarachnoid hemorrhage (aSAH) is an important type of stroke with the highest rates of mortality and disability. Recent evidence indicates that neuroinflammation plays a critical role in both early brain injury and delayed neural deterioration after aSAH, contributing to unfavorable outcomes. The neutrophil-to-lymphocyte ratio (NLR) is a peripheral biomarker that conveys information about the inflammatory burden in terms of both innate and adaptive immunity. This review summarizes relevant studies that associate the NLR with aSAH to evaluate whether the NLR can predict outcomes and serve as an effective biomarker for clinical management. We found that increased NLR is valuable in predicting the clinical outcome of aSAH patients and is related to the risk of complications such as delayed cerebral ischemia (DCI) or rebleeding. Combined with other indicators, the NLR provides improved accuracy for predicting prognosis to stratify patients into different risk categories. The underlying pathophysiology is highlighted to identify new potential targets for neuroprotection and to develop novel therapeutic strategies.

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“…After ICH, resident glial cells were activated and circulating immune cells were recruited to participate in the occurrence and development of neuroin ammation [26][27][28]. Microglia was the resident macrophage distributed in brain that could be rapidly activated to mediate neuroin ammation in response to pathological conditions, including hypoxia, infection, and brain tissue injury [29].…”

Section: Discussionmentioning

confidence: 99%

NLRP3 Inflammasome Activation Attenuates Neuronal Apoptosis by Upregulating Autophagy through AMPK/Beclin-1 Pathway after Intracerebral Hemorrhage with Ventricular Extension in Rats

Zhang¹,

Guo²,

Jia³

et al. 2021

Preprint

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BackgroundIn brain, NLRP3 inflammasome, mainly derived from macrophage/microglia, is involved in proinflammatory and neurodeficits after hemorrhage, and autophagy is vital for neuronal homeostasis and functions. Accumulating evidence suggested that NLRP3 inflammasome and autophagy played an important role in intracerebral hemorrhage (ICH). Thus, this study was designed to further explore the pathogenesis of neurodeficits after in posthemorrhagic hydrocephalus.MethodsAutologous blood injection model was induced to mimic ICH with ventricular extension (ICH-IVH) in Sprague-Dawley rats. To elucidate the underlying mechanism, the NLRP3 inflammasome inhibitor MCC950 was administered abdominally at 1 h after ICH-IVH. Magnetic resonance imaging, neurobehavioral tests, immunofluorescence, western blotting, Fluoro-Jade C- staining, Tunel staining, and Quantitative RNA Sequencing were performed.ResultsIn the acute phase of ICH-IVH, both the expression of NLRP3 inflammasome and the autophagy of neurons were upregulated. The activated NLRP3 in macrophage/microglia promoted the release of IL-1β to extracellular, which contributed to excessive autophagy, leading to neurons apoptosis both in vivo and in vitro. AMPK/Beclin-1 pathway played an important role in NLRP3-related neurons autophagy. Using MCC950(NLRP3 inflammasome specific inhibitor) treatment after ICH-IVH significantly reduced ventricles dilation, improved neurofunction, down-regulated the release of IL-1β, and alleviated neuroinflammation and excessive autophagy.ConclusionsOur finding demonstrated that NLRP3 inflammasome activated in microglia/macrophage aggravated neurological outcomes and neuronal apoptosis by upregulating autophagy after ICH-IVH, which was partly mediated by the AMPK/Beclin-1 pathway. Therefore, inhibiting the activation of NLRP3 may be a potential therapeutic strategy for the neurodeficits of ICH-IVH patients.

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Inflammatory Pathways Following Subarachnoid Hemorrhage

Cited by 48 publications

References 226 publications

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

The Role of the Blood Neutrophil-to-Lymphocyte Ratio in Aneurysmal Subarachnoid Hemorrhage

NLRP3 Inflammasome Activation Attenuates Neuronal Apoptosis by Upregulating Autophagy through AMPK/Beclin-1 Pathway after Intracerebral Hemorrhage with Ventricular Extension in Rats

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