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

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 PGE2 EP1 Receptor in Intracerebral Hemorrhage-Induced Brain Injury

Neurotoxicity Research ◽

10.1007/s12640-013-9410-7 ◽

2013 ◽

Vol 24 (4) ◽

pp. 549-559 ◽

Cited By ~ 19

Author(s):

Nilendra Singh ◽

Bo Ma ◽

Christopher Charles Leonardo ◽

Abdullah Shafique Ahmad ◽

Shuh Narumiya ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

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 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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Role of NADPH oxidase in the brain injury of intracerebral hemorrhage

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2005.03292.x ◽

2005 ◽

Vol 94 (5) ◽

pp. 1342-1350 ◽

Cited By ~ 82

Author(s):

Jiping Tang ◽

Jun Liu ◽

Changman Zhou ◽

Dmitry Ostanin ◽

Matthew B. Grisham ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Nadph Oxidase ◽

The Brain

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Role of flunarizine hydrochloride in secondary brain injury following intracerebral hemorrhage in rats

International Journal of Immunopathology and Pharmacology ◽

10.1177/0394632017742224 ◽

2017 ◽

Vol 30 (4) ◽

pp. 413-419 ◽

Cited By ~ 4

Author(s):

Jianping Niu ◽

Rui Hu

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Water Content ◽

Cell Apoptosis ◽

Akt Pathway ◽

Secondary Brain Injury ◽

Brain Water Content ◽

Hematoma Volume ◽

Brain Water

This study aimed to explore the role and mechanism(s) of flunarizine hydrochloride in the intracerebral hemorrhage (ICH) rats. The 32 adult male Sprague Dawley (SD) rats were randomly assigned into four groups: control group, sham group, ICH group, and FLU + ICH group. The effects of flunarizine hydrochloride were assessed on the basis of hematoma volume, blood–brain barrier (BBB) integrity, and brain water content in the ICH rat models. The role of flunarizine hydrochloride in cell recovery was assessed by behavioral scores, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot assay. Involvement of PI3K/AKT pathway in exerting the effect of flunarizine hydrochloride was also determined. Results showed that the hematoma volume, BBB integrity, and brain water content were significantly decreased in the FLU + ICH group. Cell apoptosis significantly increased in the ICH model group, while flunarizine hydrochloride decreased this increase. The expressions of glial cell line-derived neurotrophic factor (GDNF), neuroglobin (NGB), and p-AKT were increased after flunarizine hydrochloride treatment in ICH rats. In conclusion, flunarizine hydrochloride has protective effects against ICH by reducing brain injury, cell apoptosis, and the activation of P13K/AKT pathway. These findings provide a theoretical basis for the treatment of flunarizine hydrochloride in ICH.

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