Role of PGE2 EP1 Receptor in Intracerebral Hemorrhage-Induced Brain Injury

Background: Spontaneous intracerebral hemorrhage (ICH) is the deadliest and most debilitating form of stroke with a first year mortality rate as high as 50% to 60%. Role of prostaglandin E2 (PGE2) receptor EP1 has been extensively studies in ischemic stroke; however, the precise role of this receptor in intracerebral hemorrhage-induced brain injury is unknown. Therefore, in this study we determined the role of the EP1 receptor in collagenase-induced hemorrhagic stroke. Methods: ICH was induced randomly in 2.0-2.5 month old male C57BL/6 wildtype (WT) and EP1 knockout (EP1-/-) mice by intrastriatal injection of collagenase. Functional outcomes including neurologic deficits, rotarod performance, open field activity, and adhesive removal performance were evaluated at 72h post ICH. Hematoma volume, and cell survival and death, were assessed using cresyl violet and Fluoro-Jade staining respectively. Microglial activation was estimated using Iba1 immunoreactivity. Phagocytosis was assessed with fluorescently-labeled microspheres injected into the site of the hematoma and at the end of the survival time Iba1 immunoreactivity was used to label cells with microspheres. Values are expressed in (mean±SEM) and the number of cells/field was provided by averaging four different regions surrounding the hematoma. Results: Following 72h post injury, EP1-/- mice showed worsened outcomes compared to the WT mice. The results revealed elevated neurological and sensorimotor deficits and exacerbated hematoma volume. Fluoro-Jade staining showed significantly increased numbers of degenerating neurons and reduced neuronal survival in EP1-/- as compared with the WT mice. The in vivo phagocytic behavior of microglial cells in WT and EP1-/- suggested that the number of microspheres incorporated into Iba1-positive cells was 145.4±15.4% greater in WT than in EP1-/- mice. Conclusion: These results suggest that, the deletion of PGE2 EP1 receptor results in augmented hemorrhagic brain injury partially through reduced phagocytosis.[Supported by NIH R01 funds (SD)]

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The role of complement in brain injury following intracerebral hemorrhage: A review

Experimental Neurology ◽

10.1016/j.expneurol.2021.113654 ◽

2021 ◽

pp. 113654

Author(s):

Katherine Holste ◽

Fan Xia ◽

Hugh J.L. Garton ◽

Shu Wan ◽

Ya Hua ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage

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Correction to: Intracerebral Hemorrhage–Induced Brain Injury in Rats: the Role of Extracellular Peroxiredoxin 2

Translational Stroke Research ◽

10.1007/s12975-019-00720-z ◽

2019 ◽

Vol 11 (6) ◽

pp. 1364-1365

Author(s):

Liheng Bian ◽

Jingwei Zhang ◽

Ming Wang ◽

Richard F. Keep ◽

Guohua Xi ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Peroxiredoxin 2

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Intracerebral Hemorrhage–Induced Brain Injury in Rats: the Role of Extracellular Peroxiredoxin 2

Translational Stroke Research ◽

10.1007/s12975-019-00714-x ◽

2019 ◽

Vol 11 (2) ◽

pp. 288-295 ◽

Cited By ~ 6

Author(s):

Liheng Bian ◽

Jingwei Zhang ◽

Ming Wang ◽

Richard F. Keep ◽

Guohua Xi ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Peroxiredoxin 2

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Spreading depolarizations in patients with spontaneous intracerebral hemorrhage: Association with perihematomal edema progression

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16651269 ◽

2016 ◽

Vol 37 (5) ◽

pp. 1871-1882 ◽

Cited By ~ 16

Author(s):

Raimund Helbok ◽

Alois Josef Schiefecker ◽

Christian Friberg ◽

Ronny Beer ◽

Mario Kofler ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Electrode Placement ◽

Secondary Brain Injury ◽

Spontaneous Intracerebral Hemorrhage ◽

Strip Electrode ◽

Hematoma Evacuation ◽

Perihematomal Edema ◽

Pathophysiologic Mechanisms

Pathophysiologic mechanisms of secondary brain injury after intracerebral hemorrhage and in particular mechanisms of perihematomal-edema progression remain incompletely understood. Recently, the role of spreading depolarizations in secondary brain injury was established in ischemic stroke, subarachnoid hemorrhage and traumatic brain injury patients. Its role in intracerebral hemorrhage patients and in particular the association with perihematomal-edema is not known. A total of 27 comatose intracerebral hemorrhage patients in whom hematoma evacuation and subdural electrocorticography was performed were studied prospectively. Hematoma evacuation and subdural strip electrode placement was performed within the first 24 h in 18 patients (67%). Electrocorticography recordings started 3 h after surgery (IQR, 3–5 h) and lasted 157 h (median) per patient and 4876 h in all 27 patients. In 18 patients (67%), a total of 650 spreading depolarizations were observed. Spreading depolarizations were more common in the initial days with a peak incidence on day 2. Median electrocorticography depression time was longer than previously reported (14.7 min, IQR, 9–22 min). Postoperative perihematomal-edema progression (85% of patients) was significantly associated with occurrence of isolated and clustered spreading depolarizations. Monitoring of spreading depolarizations may help to better understand pathophysiologic mechanisms of secondary insults after intracerebral hemorrhage. Whether they may serve as target in the treatment of intracerebral hemorrhage deserves further research.

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Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

PLoS ONE ◽

10.1371/journal.pone.0113689 ◽

2014 ◽

Vol 9 (11) ◽

pp. e113689 ◽

Cited By ~ 13

Author(s):

Alexander V. Glushakov ◽

Jawad A. Fazal ◽

Shuh Narumiya ◽

Sylvain Doré

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Prostaglandin E2 ◽

Ep1 Receptor

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IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage

Stroke ◽

10.1161/strokeaha.119.028638 ◽

2020 ◽

Vol 51 (3) ◽

pp. 967-974 ◽

Cited By ~ 9

Author(s):

Samuel X. Shi ◽

Yu-Jing Li ◽

Kaibin Shi ◽

Kristofer Wood ◽

Andrew F. Ducruet ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Autologous Blood ◽

Brain Slices ◽

Neurological Deficits ◽

Transgenic Mouse Line ◽

Il Interleukin ◽

Targeted Expression ◽

Interleukin 15

Background and Purpose— Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods— Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15 tg ). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results— In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15 tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15 tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1β, and TNF-α is markedly increased in GFAP-IL-15 tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15 tg mice. Conclusions— Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.

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Abstract W P260: Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

Stroke ◽

10.1161/str.46.suppl_1.wp260 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Alexander V Glushakov ◽

Jawad A Fazal ◽

Shuh Narumiya ◽

Sylvain Dore

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Young Adult ◽

Brain Injuries ◽

Neurological Deficits ◽

Cortical Lesions ◽

Brain Pathology ◽

Adult Mice ◽

Ep1 Receptor

Introduction: Brain injuries promote upregulation of so-called proinflammatory prostaglandin E2 leading to overactivation of a class of its cognate G-protein coupled receptors, notably EP1, which is considered as a promising target for treatment of ischemic stroke and, possibly, other neurological disorders involving excitotoxicity. However, our recent data suggest that of EP1 receptor in intracerebral hemorrhage may play a protective role. The goal of this study was to investigate a translational potential of EP1 receptor for treatment of traumatic brain injury (TBI). Methods: The acute brain injury was induced using controlled cortical impact (CCI) in wildtype (WT) and genetic EP1 receptor knockout mice (EP1-/-). Neurological deficit scores (NDS) and anatomical brain pathology were accessed at 48h after injury. Results: CCI resulted in significant cortical lesions, localized hippocampal edema and neurological deficits compared to animals from sham group underwent craniotomy only. The NDS after CCI were significantly higher in older mice (7-11mo) compared to young adult animals (2-4mo) in both WT and EP1-/- groups. Treatment with a selective antagonist SC-51089 with repeated doses of 20-100μg/kg after CCI had no significant effects on cortical lesions, hippocampal edema and NDS in young adult mice of both WT and EP1-/- genotypes. Post-treatment with 17-pt-PGE2 (300μg/kg) had no significant effects on anatomical brain pathology in young adult mice, but improved NDS at 24h in WT but not in EP1-/- mice. Immunohistochemistry revealed significant increases in GFAP and Iba1 immunoreactivity in selected brain regions surrounding injury suggesting astrogliosis and microglia activation. EP1 receptor knockout had no effects on GFAP and Iba1 expression in young adult mice, whereas lead to a significant attenuation of GFAP immunoreactivity in older mice. Conclusions: This study provides, for the first time, a clarification on the role of EP1 receptor in a preclinical model of contusive TBI. The results suggest that EP1 receptor might be involved in complex pathways differentially associated with neurological deficits. In addition, this study provides further clarification on clinical use of EP1 receptor ligands for treatment of acute brain injuries.

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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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