scholarly journals PGE2-EP3 signaling exacerbates intracerebral hemorrhage outcomes in 24-mo-old mice

2016 ◽  
Vol 310 (11) ◽  
pp. H1725-H1734 ◽  
Author(s):  
Jenna L. Leclerc ◽  
Andrew S. Lampert ◽  
Matthew A. Diller ◽  
Sylvain Doré
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Functional Recovery ◽  
Fine Motor ◽  
Prostaglandin E ◽  
Receptor Subtype ◽  
Ep Receptor ◽  
Ep3 Receptor ◽  
Old Mice ◽  
Young Mice

With the population aging at an accelerated rate, the prevalence of stroke and financial burden of stroke-related health care costs are expected to continue to increase. Intracerebral hemorrhage (ICH) is a devastating stroke subtype more commonly affecting the elderly population, who display increased mortality and worse functional outcomes compared with younger patients. This study aimed to investigate the contribution of the prostaglandin E2 (PGE2) E prostanoid (EP) receptor subtype 3 in modulating anatomical outcomes and functional recovery following ICH in 24-mo-old mice. EP3 is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE2-EP3 axis exacerbates ICH outcomes in young mice. Here, we show that EP3 receptor deletion results in 17.9 ± 6.1% less ICH-induced brain injury ( P < 0.05) and improves neurological functional recovery ( P < 0.01), as identified by lower neurological deficit scores, decreased resting time, and more gross and fine motor movements. Immunohistological staining was performed to investigate possible mechanisms of EP3-mediated neurotoxicity. Identified mechanisms include reduced blood accumulation and modulation of angiogenic and astroglial responses. Using this aged cohort of mice, we have confirmed and extended our previous results in young mice demonstrating the deleterious role of the PGE2-EP3 signaling axis in modulating brain injury and functional recovery after ICH, further supporting the notion of the EP3 receptor as a putative therapeutic avenue for the treatment of ICH.

scholarly journals Celecoxib Induces Functional Recovery after Intracerebral Hemorrhage with Reduction of Brain Edema and Perihematomal Cell Death

2004 ◽  
Vol 24 (8) ◽  
pp. 926-933 ◽  
Author(s):  
Kon Chu ◽  
Sang-Wuk Jeong ◽  
Keun-Hwa Jung ◽  
So-Young Han ◽  
Soon-Tae Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Functional Recovery ◽  
Autologous Blood ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Behavioral Tests ◽  
Adult Rats ◽  
Cox 2

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood–injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.

scholarly journals Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage

2021 ◽  
Vol 6 (56) ◽  
pp. eabd6279
Author(s):  
Michael H. Askenase ◽  
Brittany A. Goods ◽  
Hannah E. Beatty ◽  
Arthur F. Steinschneider ◽  
Sofia E. Velazquez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Injury ◽  
Immune Responses ◽  
Intracerebral Hemorrhage ◽  
Human Brain ◽  
Inflammatory Factors ◽  
Lipid Mediator ◽  
Prostaglandin E ◽  
Anti Inflammatory ◽  
Over Time

Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14+ monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE2, which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.

scholarly journals Prostaglandin E2EP2 Receptor Deletion Attenuates Intracerebral Hemorrhage-Induced Brain Injury and Improves Functional Recovery

ASN NEURO ◽  
2015 ◽  
Vol 7 (2) ◽  
pp. 175909141557871 ◽  
Author(s):  
Jenna L. Leclerc ◽  
Andrew S. Lampert ◽  
Matthew A. Diller ◽  
Joshua B. Immergluck ◽  
Sylvain Doré
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Functional Recovery

A self-assembling nanomaterial reduces acute brain injury and enhances functional recovery in a rat model of intracerebral hemorrhage

2015 ◽  
Vol 11 (3) ◽  
pp. 611-620 ◽  
Author(s):  
Lynn Yan-Hua Sang ◽  
Yu-Xiang Liang ◽  
Yue Li ◽  
Wai-Man Wong ◽  
David Kiong-Chiu Tay ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Functional Recovery ◽  
Rat Model ◽  
Acute Brain Injury ◽  
Self Assembling

scholarly journals Iron Toxicity in Mice with Collagenase-Induced Intracerebral Hemorrhage

2010 ◽  
Vol 31 (5) ◽  
pp. 1243-1250 ◽  
Author(s):  
He Wu ◽  
Tao Wu ◽  
Xueying Xu ◽  
Jessica Wang ◽  
Jian Wang
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Neuronal Death ◽  
Neutrophil Infiltration ◽  
Iron Chelator ◽  
Iron Toxicity ◽  
Iron Accumulation ◽  
Neurologic Function ◽  
Old Mice ◽  
Intrastriatal Injection

Intracerebral hemorrhage (ICH) is a devastating form of stroke. In this study, we examined the efficacy of deferoxamine (DFX), an iron chelator, after collagenase-induced ICH in 12-month-old mice. Intracerebral hemorrhage was induced by intrastriatal injection of collagenase. Deferoxamine (200 mg/kg, intraperitoneal) or vehicle was administrated 6 hours after ICH and then every 12 hours for up to 3 days. Neurologic deficits were examined on days 1 and 3 after ICH. Mice were killed after 1 or 3 days of DFX treatment for examination of iron deposition, neuronal death, oxidative stress, microglia/astrocyte activation, neutrophil infiltration, brain injury volume, and brain edema and swelling. Collagenase-induced ICH resulted in iron overload in the perihematomal region on day 3. Systemic administration of DFX decreased iron accumulation and neuronal death, attenuated production of reactive oxygen species, and reduced microglial activation and neutrophil infiltration without affecting astrocytes. Although DFX did not reduce brain injury volume, edema, or swelling, it improved neurologic function. Results of our study indicate that iron toxicity contributes to collagenase-induced hemorrhagic brain injury and that reducing iron accumulation can reduce neuronal death and modestly improve functional outcome after ICH in mice.

scholarly journals Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury

2015 ◽  
Vol 36 (6) ◽  
pp. 1059-1074 ◽  
Author(s):  
Xiaoning Han ◽  
Xi Lan ◽  
Qiang Li ◽  
Yufeng Gao ◽  
Wei Zhu ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Rho Kinase ◽  
Receptor Activation ◽  
Prostaglandin E ◽  
Arterial Blood ◽  
Receptor Inhibition ◽  
Ep3 Receptor

Prostaglandin E2 EP3 receptor is the only prostaglandin E2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68+ microglia, but increased the number of Ym-1+ M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase–mediated cytotoxicity and proinflammatory responses.

scholarly journals hysiological and Biochemical Changes in NRF2 Pathway in Aged Animals Subjected to Brain Injury

2021 ◽  
Vol 55 (2) ◽  
pp. 160-179
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Injuries ◽  
Focal Cerebral Ischemia ◽  
The Elderly ◽  
Artery Occlusion ◽  
Biochemical Changes ◽  
Old Mice ◽  
Young Mice

Background/Aims: Oxidative stress plays a key role in aging, which in turn represents a substantial risk factor for brain injuries. The aim of the present study was to investigate the differences in physiological and biochemical changes in the brain during injury-related inflammation and oxidative stress, comparing young and old mice. Methods: Young and old mice were subjected to focal cerebral ischemia induced by transient middle cerebral artery occlusion or to traumatic brain injury performed by a controlled cortical impactor. At the end of both experiments, mice were sacrificed 24h after injuries and brains were collected to perform biochemical analysis. Results: In both ischemic stroke and traumatic brain injury, aging has not only led to damage-induced worsening of motor function and behavioural changes but also increased of infarct area compared to young animals. Moreover, aged mice show increased evidence of oxidative stress and reduced antioxidant capacity when compared to younger animals, as demonstrated by Nrf2-Keap1 signalling pathway and lower expression of antioxidant enzymes, such as HO-1, SOD-1 and GSH-Px. Additionally, brain tissues collected from elderly mice showed an increased IκB-α degradation into the cytoplasm and consequently NF-κB translocation into the nucleus, compared to young mice subjected to same injuries. The elderly mice showed significantly higher levels of iNOS and CoX-2 expression than the young mice, as well as higher levels of inflammatory cytokines such as TNFα, IL-1β, and IL-6 after MCAO and TBI. Conclusion: Preserving and keeping the NRF-2 pathway active counteracts the onset of oxidative stress and consequent inflammation after ischemic and traumatic brain insult, particularly in the elderly. Not only that, NRF-2 pathway could represent a possible therapeutic target in the management of brain injuries.

Abstract TP346: Pge2 Ep1-4 Temporospatial Expression Level Changes in the Brain After Intracerebral Hemorrhage in Young, Aged, and Ep1 Deficient Mice Suggests Cross-talk Interactions

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Jenna L Leclerc ◽  
Andrew R Fadool ◽  
Julie C Bailes ◽  
Chase Chambers ◽  
Sylvain Doré
Keyword(s):  
Intracerebral Hemorrhage ◽  
Cross Talk ◽  
Time Course ◽  
Expression Profiles ◽  
Receptor Expression ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Expression Levels ◽  
Ep Receptors ◽  
Ep Receptor

Intracerebral hemorrhage (ICH) is the most severe form of stroke with the highest mortality. Neuroinflammation contributes to ICH-induced brain injury and the upregulation of prostaglandin E 2 (PGE 2 ) has been implicated in modulating these deleterious pathways. PGE 2 acts mainly on four G-protein-coupled E Prostanoid (EP) receptors, EP1-4, each having different downstream pathways, tissue distributions, and expression profiles. Our previous studies demonstrate that EP1 receptor deletion promotes injury following ICH; whereas, deletion of EP2 and EP3 is neuroprotective in an equivalent approach. Here, we aimed to investigate the time course, brain sub-region expression profile, and relative level of EP1-4 mRNA expression in young (5-7mo) and aged (12-13mo) wildtype (WT) and EP1-/- mice. Following ICH or sham surgery, EP1-4 mRNA levels were assessed by RT-qPCR whereby the relative fold change of the gene of interest were determined using the reference gene Tbp and the 2 -ΔΔCT method relative to the control. Minimal EP1-4 expression changes are seen at 24h after ICH; although, EP2 (p=0.036) and EP4 (p=0.066) are 1.6X increased in the cortex of young WT mice. At 72h post-ICH, EP1 is 3.9x elevated in the cortex (p=0.0003) and 4.6x in the striatum (p=0.012). EP3 is also 1.6x elevated in the cortex (p=0.044). In the contralateral hemisphere, a mean 2.4x increase of EP1-4 (p<0.01) expression is seen. In contrast, at 72h after ICH, EP1-/- mice have 0.53x reduced EP3 in the cortex (p=0.030) and 0.68x and 0.71x decreased EP3 (p=0.016) and EP4 (p=0.049), respectively, in the contralateral. Aged EP1 -/- mice show significantly decreased expression levels of EP2-4 in nearly all areas. Due to the contralateral differences, basal expression levels of EP2-4 were investigated in the EP1-/- mice, where EP2 is 2.6x, 3.4x, and 3.8x increased in the cortex, hippocampus, and cerebellum; whereas, EP3 trended oppositely. These data indicate a cross talk between EP1 and the other EP receptors pre- and post-ICH and an association between age and EP receptor expression levels. A better understanding of EP receptor localization and dynamic expression levels after ICH will spark the development of effective pharmacological treatments. Funding: NIH F31NS086441 (JLL) and R01NS046400 (SD)

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