Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice

Inflammatory responses mediated by prostaglandins such as PGE2 may contribute to secondary brain injury after intracerebral hemorrhage (ICH). However, the cell-specific signaling by PGE2 receptor EP2 differs depending on whether the neuropathic insult is acute or chronic. Using genetic and pharmacologic approaches, we investigated the role of EP2 receptor in two mouse models of ICH induced by intrastriatal injection of collagenase or autologous arterial whole blood. We used middle-aged male mice to enhance the clinical relevance of the study. EP2 receptor was expressed in neurons but not in astrocytes or microglia after collagenase-induced ICH. Brain injury after collagenase-induced ICH was associated with enhanced cellular and molecular inflammatory responses, oxidative stress, and matrix metalloproteinase (MMP)-2/9 activity. EP2 receptor deletion exacerbated brain injury, brain swelling/edema, neuronal death, and neurobehavioral deficits, whereas EP2 receptor activation by the highly selective agonist AE1-259-01 reversed these outcomes. EP2 receptor deletion also exacerbated brain edema and neurologic deficits in the blood ICH model. These findings support the premise that neuronal EP2 receptor activation by PGE2 protects brain against ICH injury in middle-aged mice through its anti-inflammatory and anti-oxidant effects and anti-MMP-2/9 activity. PGE2/EP2 signaling warrants further investigation for potential use in ICH treatment.

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Abstract W P246: Prostaglandin E2 EP2 Receptor Signaling Aggravates Intracerebral Hemorrhage-Induced Brain Injury

Stroke ◽

10.1161/str.46.suppl_1.wp246 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Jenna L Leclerc ◽

Joshua Immergluck ◽

Andrew Lampert ◽

Matthew Diller ◽

Sylvain Doré

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Prostaglandin E2 ◽

Inflammatory Responses ◽

Neuronal Cultures ◽

Secondary Brain Injury ◽

Lesion Volume ◽

Receptor Signaling ◽

Ep2 Receptor

Inflammation after intracerebral hemorrhage (ICH) is a key component to secondary brain injury, a major cause of morbidity and disability after ICH. Prostaglandin E2 (PGE 2 ) plays an important role in modulating inflammatory responses and in many neurologic disorders. PGE 2 binds with high affinity to the G-protein-coupled receptors EP1, EP2, EP3, and EP4, which collectively mediate its neuroimmunomodulatory effects. We and others have documented that the EP2 receptor mediates the neuroprotective properties of PGE 2 in neuronal cultures and in the middle cerebral artery occlusion model of ischemia/reperfusion-induced brain injury. The present study aimed to investigate the role of EP2 receptor signaling on anatomical and functional outcomes after ICH. The collagenase model was used to induce an ICH in wildtype (WT) and EP2 -/- mice (n=8-11/group). After 72h, mice were sacrificed and brains collected for Cresyl Violet staining and lesion volume quantification. The EP2 -/- displayed significantly reduced lesion volumes when compared to WT controls (p<0.005). The EP2 -/- also showed reduced cortical and striatal microglial activation (p<0.05), and less cortical astrocyte activation (p<0.05). Collectively, these results suggest that PGE 2 -EP2 receptor signaling aggravates ICH-induced brain injury in vivo, which is in contrast to previous reports in stroke models, highlighting the dynamic role of the EP2 receptor in modulating inflammatory responses following brain damage. Further investigations are necessary in order to identify the mechanism of EP2-mediated hematoma resolution. Additional studies using a selective EP2 receptor antagonist could lead to the development of improved drugs that minimize the side effects often associated with anti-inflammatory medications in order to help prevent or improve neurologic recovery following ICH.

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lncRNA Mtss1 promotes inflammatory responses and secondary brain injury after intracerebral hemorrhage by targeting miR-709 in mice

Brain Research Bulletin ◽

10.1016/j.brainresbull.2020.04.017 ◽

2020 ◽

Vol 162 ◽

pp. 20-29 ◽

Cited By ~ 1

Author(s):

Jia-Xiang Chen ◽

Yi-Ping Wang ◽

Xin Zhang ◽

Guo-Xiong Li ◽

Kuang Zheng ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Inflammatory Responses ◽

Secondary Brain Injury

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Mitochondria: Novel Mechanisms and Therapeutic Targets for Secondary Brain Injury After Intracerebral Hemorrhage

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.615451 ◽

2021 ◽

Vol 12 ◽

Author(s):

Weixiang Chen ◽

Chao Guo ◽

Hua Feng ◽

Yujie Chen

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Hemorrhagic Stroke ◽

Secondary Brain Injury ◽

Valuable Insight ◽

Potential Therapeutic Target ◽

Pathological Mechanism ◽

Clinical Strategies ◽

Inflammatory Activation ◽

Insight Into

Intracerebral hemorrhage (ICH) is a destructive form of stroke that often results in death or disability. However, the survivors usually experience sequelae of neurological impairments and psychiatric disorders, which affect their daily functionality and working capacity. The recent MISTIE III and STICH II trials have confirmed that early surgical clearance of hematomas does not improve the prognosis of survivors of ICH, so it is vital to find the intervention target of secondary brain injury (SBI) after ICH. Mitochondrial dysfunction, which may be induced by oxidative stress, neuroinflammation, and autophagy, among others, is considered to be a novel pathological mechanism of ICH. Moreover, mitochondria play an important role in promoting neuronal survival and improving neurological function after a hemorrhagic stroke. This review summarizes the mitochondrial mechanism involved in cell death, reactive oxygen species (ROS) production, inflammatory activation, blood–brain barrier (BBB) disruption, and brain edema underlying ICH. We emphasize the potential of mitochondrial protection as a potential therapeutic target for SBI after stroke and provide valuable insight into clinical strategies.

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RAB7L1 Participates in Secondary Brain Injury Induced by Experimental Intracerebral Hemorrhage in Rats

Journal of Molecular Neuroscience ◽

10.1007/s12031-020-01619-3 ◽

2020 ◽

Vol 71 (1) ◽

pp. 9-18

Author(s):

Xiaoxing Tan ◽

Yuchong Wei ◽

Jie Cao ◽

Degang Wu ◽

Niansheng Lai ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Secondary Brain Injury

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Different responses after intracerebral hemorrhage between young and early middle-aged mice

Neuroscience Letters ◽

10.1016/j.neulet.2020.135249 ◽

2020 ◽

Vol 735 ◽

pp. 135249

Author(s):

Keita Kinoshita ◽

Ryo Ohtomo ◽

Hajime Takase ◽

Gen Hamanaka ◽

Kelly K. Chung ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Middle Aged ◽

Aged Mice

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AdipoRon Protects Against Secondary Brain Injury After Intracerebral Hemorrhage via Alleviating Mitochondrial Dysfunction: Possible Involvement of AdipoR1–AMPK–PGC1α Pathway

Neurochemical Research ◽

10.1007/s11064-019-02794-5 ◽

2019 ◽

Vol 44 (7) ◽

pp. 1678-1689 ◽

Cited By ~ 1

Author(s):

Jun Yu ◽

Jingwei Zheng ◽

Jianan Lu ◽

Zeyu Sun ◽

Zefeng Wang ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Mitochondrial Dysfunction ◽

Secondary Brain Injury

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Association between neutrophil to lymphocyte ratio and blood glucose level at admission in patients with spontaneous intracerebral hemorrhage

Scientific Reports ◽

10.1038/s41598-019-52214-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Fan Zhang ◽

Yanming Ren ◽

Wei Fu ◽

Yuelong Wang ◽

Juan Qian ◽

...

Keyword(s):

Regression Analysis ◽

Blood Glucose ◽

Intracerebral Hemorrhage ◽

Blood Glucose Level ◽

Glucose Level ◽

Inflammatory Responses ◽

Neutrophil To Lymphocyte Ratio ◽

Secondary Brain Injury ◽

Imaging Features ◽

Lymphocyte Ratio

Abstract Previous studies indicated that both inflammatory responses and hyperglycemia are involved in the similar pathophysiological mechanisms after onset of intracerebral hemorrhage (ICH). However the relationship between hyperglycemia and inflammation remains unknown. We aim to evaluate the associations of hyperglycemia with inflammation and neutrophil to lymphocyte ratio (NLR) in patients with ICH. Patients with acute ICH were retrospectively enrolled. Clinical characteristics and imaging features were obtained. The associations between outcome and laboratory biomarkers were assessed by multivariable logistic regression analysis. Spearman analysis and multiple linear regression analysis were performed to estimate the association of NLR and serum glucose. 175 patients were enrolled. Poor outcome occurred in 86 patients at 30 days. Elevated blood glucose level (BGL) and NLR were strongly associated with outcome in patients with ICH. Moreover, combined NLR-BGL exhibited a better predictive accuracy compared with the peripheral leukocyte counts. Furthermore, there was a robust association between BGL and NLR. We first demonstrated both of NLR and BGL were independently associated with each other. Our results indicate that inflammatory responses and the pathological process of hyperglycemia may influence each other by several complex pathological mechanisms and have a mutual promoting effect to secondary brain injury.

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Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20916860 ◽

2020 ◽

pp. 0271678X2091686 ◽

Cited By ~ 4

Author(s):

Fang Shen ◽

Xiang Xu ◽

Zhengquan Yu ◽

Haiying Li ◽

Haitao Shen ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Protein Level ◽

Rna Binding ◽

Neuronal Degeneration ◽

Binding Protein ◽

Neurological Diseases ◽

Rna Binding Protein ◽

Micro Rna ◽

Secondary Brain Injury

RNA-binding protein fox-1 homolog 1 (Rbfox-1), an RNA-binding protein in neurons, is thought to be associated with many neurological diseases. To date, the mechanism on which Rbfox-1 worsens secondary cell death in ICH remains poorly understood. In this study, we aimed to explore the role of Rbfox-1 in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and to identify its underlying mechanisms. We found that the expression of Rbfox-1 in neurons was significantly increased after ICH, which was accompanied by increases in the binding of Rbfox-1 to Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) mRNA and the protein level of CaMKIIα. In addition, when exposed to exogenous upregulation or downregulation of Rbfox-1, the protein level of CaMKIIα showed a concomitant trend in brain tissue, which further suggested that CaMKIIα is a downstream-target protein of Rbfox-1. The upregulation of both proteins caused intracellular-Ca2+ overload and neuronal degeneration, which exacerbated brain damage. Furthermore, we found that Rbfox-1 promoted the expression of CaMKIIα via blocking the binding of micro-RNA-124 to CaMKIIα mRNA. Thus, Rbfox-1 is expected to be a promising therapeutic target for SBI after ICH.

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