Abstract WP309: Association of Molecular Markers with Perihematomal Edema and Clinical Outcome in Intracerebral Hemorrhage

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Na Li ◽  
Yan Fang Liu ◽  
Li Ma ◽  
Hans Worthmann ◽  
Peter Raab ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Brain Injury ◽  
Clinical Outcome ◽  
Intracerebral Hemorrhage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Stroke Severity ◽  
Secondary Brain Injury ◽  
Hematoma Volume ◽  
Perihematomal Edema

Background and Purpose: Perihematomal edema (PHE) contributes to secondary brain injury in intracerebral hemorrhage (ICH). Increase of matrix metalloproteinases (MMPs) and growth factors (GFs) is considerably involved in blood-brain barrier disruption and neuronal cell death in ICH models. We therefore hypothesized that increased levels of these molecular markers are associated with PHE and clinical outcome in ICH patients. Methods: Fifty-nine patients with spontaneous ICH admitted within 24 hours of symptom onset were prospectively investigated. Noncontrast CT was performed on admission for diagnosis of ICH and quantification of initial hematoma volume. MRI was performed on day 3 in order to evaluate PHE. Concentrations of MMP-3, MMP-9, as well as vascular endothelial growth factor (VEGF) and Angiopoietin-1(Ang-1) on admission were determined by enzyme-linked immunosorbent assays. Clinical outcome was assessed by modified Rankin Scale (mRS) at 90days. Results: Increased MMP-3 levels were independently associated with PHE volume (P<0.05). Cytotoxic edema (CE) surrounding the hematoma was seen in 36 (61%) cases on 3-day MRI. CE did not correlate with the level of any of the biomarkers studied. Levels of MMP-3 ≥12.4 ng/ml and MMP-9 ≥192.4 ng/ml but not VEGF and Ang-1 predicted poor clinical outcome at 90 days (mRS>3) independent of stroke severity and hematoma volume at baseline (OR 25.3, P=0.035; OR 68.9, P=0.023; respectively). Conclusion: Metalloproteinases 3 and 9 seem to be significantly involved in secondary brain injury and outcome after primary ICH in humans and thus should be further evaluated as targets for therapeutic strategies in this devastating disorder.

scholarly journals Association of Molecular Markers With Perihematomal Edema and Clinical Outcome in Intracerebral Hemorrhage

Stroke ◽  
2013 ◽  
Vol 44 (3) ◽  
pp. 658-663 ◽  
Author(s):  
Na Li ◽  
Yan Fang Liu ◽  
Li Ma ◽  
Hans Worthmann ◽  
Yi Long Wang ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Clinical Outcome ◽  
Intracerebral Hemorrhage ◽  
Perihematomal Edema

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

2016 ◽  
Vol 37 (5) ◽  
pp. 1871-1882 ◽  
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.

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

2017 ◽  
Vol 30 (4) ◽  
pp. 413-419 ◽  
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.

scholarly journals Microglia as target for anti-inflammatory approaches to prevent secondary brain injury after subarachnoid hemorrhage (SAH)

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Rebecca Heinz ◽  
Susan Brandenburg ◽  
Melina Nieminen-Kelhä ◽  
Irina Kremenetskaia ◽  
Philipp Boehm-Sturm ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Neuronal Cell Death ◽  
Treatment Strategies ◽  
Neuronal Cell ◽  
Surface Expression ◽  
Receptor Activation ◽  
Sham Operation ◽  
Secondary Brain Injury ◽  
Anti Inflammatory

Abstract Background Microglia-driven cerebral spreading inflammation is a key contributor to secondary brain injury after SAH. Genetic depletion or deactivation of microglia has been shown to ameliorate neuronal cell death. Therefore, clinically feasible anti-inflammatory approaches counteracting microglia accumulation or activation are interesting targets for SAH treatment. Here, we tested two different methods of interference with microglia-driven cerebral inflammation in a murine SAH model: (i) inflammatory preconditioning and (ii) pharmacological deactivation. Methods 7T-MRI-controlled SAH was induced by endovascular perforation in four groups of C57Bl/6 mice: (i) Sham-operation, (ii) SAH naïve, (iii) SAH followed by inflammatory preconditioning (LPS intraperitoneally), and (iv) SAH followed by pharmacological microglia deactivation (colony-stimulating factor-1 receptor-antagonist PLX3397 intraperitoneally). Microglia accumulation and neuronal cell death (immuno-fluorescence), as well as activation status (RT-PCR for inflammation-associated molecules from isolated microglia) were recorded at day 4 and 14. Toll-like receptor4 (TLR4) status was analyzed using FACS. Results Following SAH, significant cerebral spreading inflammation occurred. Microglia accumulation and pro-inflammatory gene expression were accompanied by neuronal cell death with a maximum on day 14 after SAH. Inflammatory preconditioning as well as PLX3397-treatment resulted in significantly reduced microglia accumulation and activation as well as neuronal cell death. TLR4 surface expression in preconditioned animals was diminished as a sign for receptor activation and internalization. Conclusions Microglia-driven cerebral spreading inflammation following SAH contributes to secondary brain injury. Two microglia-focused treatment strategies, (i) inflammatory preconditioning with LPS and (ii) pharmacological deactivation with PLX3397, led to significant reduction of neuronal cell death. Increased internalization of inflammation-driving TLR4 after preconditioning leaves less receptor molecules on the cell surface, providing a probable explanation for significantly reduced microglia activation. Our findings support microglia-focused treatment strategies to overcome secondary brain injury after SAH. Delayed inflammation onset provides a valuable clinical window of opportunity.

scholarly journals Perihematomal Diffusion Restriction in Intracerebral Hemorrhage Depends on Hematoma Volume, But Does Not Predict Outcome

2016 ◽  
Vol 42 (3-4) ◽  
pp. 280-287 ◽  
Author(s):  
Sebastian Stösser ◽  
Hermann Neugebauer ◽  
Katharina Althaus ◽  
Albert C. Ludolph ◽  
Jan Kassubek ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Intracerebral Hemorrhage ◽  
Symptom Onset ◽  
Independent Predictor ◽  
Severe Disability ◽  
Clinical Predictors ◽  
Hematoma Volume ◽  
Diffusion Restriction ◽  
Apparent Diffusion ◽  
Perihematomal Edema

Background: Perihematomal diffusion restriction (PDR) is a frequent finding in primary intracerebral hemorrhage (ICH) on diffusion-weighted MRI. Its frequency, associated clinical and imaging findings and impact on clinical outcome are not well understood. Methods: This is a retrospective single-center analysis of 172 patients with primary ICH who received MRI within 24 h from symptom onset. PDR was defined as a reduction of apparent diffusion coefficient below 550 × 10-6 mm2/s. Multivariate regression analyses were used to assess independent imaging and clinical predictors of PDR. Clinical outcome was assessed using the modified Rankin scale (mRS) at discharge. Results: PDR was present in 88 patients (51.2%). Median PDR volume was 1.1 ml (interquartile range 0.2-4.2). Multivariate analyses identified hematoma volume as the key independent predictor of PDR. The volume of perihematomal edema, lobar hematoma location and low diastolic blood pressure at admission were further predictors. Although the occurrence of PDR correlated with in-hospital mortality (75.0 vs. 43.4%, p < 0.001) and moderately severe to severe disability or death at discharge (mRS ≥4; 56.4 vs. 27.8%, p = 0.002), PDR was not an independent predictor of clinical outcome. In contrast, hematoma volume, ventricular extension of hemorrhage and higher age independently predicted an adverse clinical outcome. Conclusions: PDR is common after primary ICH within 24 h of symptom onset. Hematoma volume was identified as the key predictor of PDR. Although PDR was associated with mortality and severe disability, this effect was confounded by established risk factors. These results do not support a role of early PDR as prognostic factor after ICH independent of hematoma volume.

Oxidative Stress: Major Threat in Traumatic Brain Injury

2018 ◽  
Vol 17 (9) ◽  
pp. 689-695 ◽  
Author(s):  
Nidhi Khatri ◽  
Manisha Thakur ◽  
Vikas Pareek ◽  
Sandeep Kumar ◽  
Sunil Sharma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mitochondrial Dysfunction ◽  
Calcium Influx ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Physical Assault ◽  
Mortality And Morbidity ◽  
Primary Injury

Background & Objective: Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity worldwide. It represents mild, moderate and severe effects of physical assault to brain which may cause sequential, primary or secondary ramifications. Primary injury can be due to the first physical hit, blow or jolt to one of the brain compartments. The primary injury is then followed by secondary injury which leads to biochemical, cellular, and physiological changes like blood brain barrier disruption, inflammation, excitotoxicity, necrosis, apoptosis, mitochondrial dysfunction and generation of oxidative stress. Apart from this, there is also an immediate increase in glutamate at the synapses following severe TBI. Excessive glutamate at synapses in turn activates corresponding NMDA and AMPA receptors that facilitate excessive calcium influx into the neuronal cells. This leads to the generation of oxidative stress which further leads to mitochondrial dysfunction, lipid peroxidation and oxidation of proteins and DNA. As a consequence, neuronal cell death takes place and ultimately people start facing some serious disabilies. Conclusion: In the present review we provide extensive overview of the role of reactive oxygen species (ROS)-induced oxidative stress and its fatal effects on brain after TBI.

scholarly journals p53-mediated neuronal cell death in ischemic brain injury

2010 ◽  
Vol 26 (3) ◽  
pp. 232-240 ◽  
Author(s):  
Li-Zhi Hong ◽  
Xiao-Yuan Zhao ◽  
Hui-Ling Zhang
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ischemic Brain Injury ◽  
Ischemic Brain

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

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.

The LPA-CDK5-Tau Pathway Mediates Neuronal Injury in an In Vitro Model of Ischemia-Reperfusion Insult

2021 ◽  
Author(s):  
Yaya Wang ◽  
Jie Zhang ◽  
Liqin Huang ◽  
Yanhong Mo ◽  
Changyu Wang ◽  
...  
Keyword(s):  
Brain Injury ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Ischemia Reperfusion ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ischemic Brain ◽  
Pathophysiological Process ◽  
Vitro Model

Abstract Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.

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