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Representative pictures of hematoma and perihematoma edema measurements. a ROIs drawn around the perimeters of the perihematoma edema and hematoma. b ROIs drawn on the frontal white matter and GP.
Source publication
Iron neurotoxicity has been linked to delayed neuronal injury and edema formation after intracerebral hemorrhage (ICH). We have previously shown that serum ferritin, an indicator of body iron load, correlates with the relative perihematoma edema volume (RPHEV) on days 3-4 after ICH. We undertook this study to directly examine the relationship betwe...
Contexts in source publication
Context 1
... of the hema- toma and perihematoma edema was assisted by adjustment of the contrast and threshold value until the hematoma consisting of a dark rim and bulk on T 2 images could be well separated from the surrounding hyperintense edematous brain tissue in terms of ap- propriate high-and low-attenuation zones [12] . The examiner then manually drew regions of interest (ROIs) by tracing the pe- rimeters of the hematoma and perihematoma edema in each slice throughout the hemorrhagic lesion ( fig. 1 a). The traced ROIs in contiguous voxels were then summed up after adjusting for the slice thickness to yield a hematoma volume and an absolute ede- ma volume (the volume of the hematoma and surrounding ede- ma) ( fig. 1 a). ...
Context 2
... examiner then manually drew regions of interest (ROIs) by tracing the pe- rimeters of the hematoma and perihematoma edema in each slice throughout the hemorrhagic lesion ( fig. 1 a). The traced ROIs in contiguous voxels were then summed up after adjusting for the slice thickness to yield a hematoma volume and an absolute ede- ma volume (the volume of the hematoma and surrounding ede- ma) ( fig. 1 a). To control for hematoma volume, we subtracted the hematoma volume from that of the absolute edema, and divided the product by the hematoma volume, to express the perihema- toma edema volume as a ratio of the associated hematoma volume (RPHEV). ...
Context 3
... intraobserv- Because the intra-and interobserver reliability measures were high, only one measurement by 1 observer (M.L.) was used for the remainder of the ROIs. ROIs were also manually drawn in the GP and frontal white matter, contralateral to the hematoma ( fig. 1 b). The GP was cho- sen because it has the highest iron content in the brain and is eas- ily visible on T 2 images [13][14][15] . ...
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Background:
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Background
Intracerebral hemorrhage (ICH) induces microglial activation and the release of inflammatory cytokines, leading to inflammation in the brain. IRAK4, an essential component of the MyD88-dependent pathway, activates subsets of divergent signaling pathways in inflammation.
Methods
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Citations
... ICH. 51,55,56 Numerous reports have also revealed the crucial role of iron in neuronal death after ICH. 18,52,57,58 Thus, how to inhibit cellular iron uptake still needs further investigation. ...
Objective
Neuronal precursor cells expressed developmentally down‐regulated 4 (Nedd4) are believed to play a critical role in promoting the degradation of substrate proteins and are involved in numerous biological processes. However, the role of Nedd4 in intracerebral hemorrhage (ICH) remains unknown. This study aims to investigate the regulatory role of Nedd4 in the ICH model.
Methods
Male C57BL/6J mice were induced with ICH. Subsequently, the levels of glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, as well as the expression of divalent metal transporter 1 (DMT1) and Nedd4 were assessed after ICH. Furthermore, the impact of Nedd4 overexpression was evaluated through analyses of hematoma area, ferroptosis, and neurobehavioral function. The mechanism underlying Nedd4‐mediated degradation of DMT1 was elecidated using immunoprecipitation (IP) after ICH.
Results
Upon ICH, the level of DMT1 in the brain increased, but decreased when Nedd4 was overexpressed using Lentivirus, suggesting a negative correlation between Nedd4 and DMT1. Additionally, the degradation of DMT1 was inhibited after ICH. Furthermore, it was found that Nedd4 can interact with and ubiquitinate DMT1 at lysine residues 6, 69, and 277, facilitating the degradation of DMT1. Functional analysis indicated that overexpression of Nedd4 can alleviate ferroptosis and promote recovery following ICH.
Conclusion
The results demonstrated that ferroptosis occurs via the Nedd4/DMT1 pathway during ICH, suggesting it potential as a valuable target to inhibit ferroptosis for the treatment of ICH.
... 1,[6][7][8][9] Animal studies have demonstrated that the formation of a blood clot within the hematoma is directly linked to the formation of cerebral edema. [10][11][12][13] Thus, there is a dynamic interaction involving coagulation. On the one hand, nonclotted blood results in less pronounced edema and thus a potentially better outcome. ...
BACKGROUND
The dynamics of blood clot (combination of Hb [hemoglobin], fibrin, and a higher concentration of aggregated red blood cells) formation within the hematoma of an intracerebral hemorrhage is not well understood. A quantitative neuroimaging method of localized coagulated blood volume/distribution within the hematoma might improve clinical decision-making.
METHODS
The deoxyhemoglobin of aggregated red blood cells within extravasated blood exhibits a higher magnetic susceptibility due to unpaired heme iron electrons. We propose that coagulated blood, with higher aggregated red blood cell content, will exhibit (1) a higher positive susceptibility than noncoagulated blood and (2) increase in fibrin polymerization–restricted localized diffusion, which can be measured noninvasively using quantitative susceptibility mapping and diffusion tensor imaging. In this serial magnetic resonance imaging study, we enrolled 24 patients with acute intracerebral hemorrhage between October 2021 to May 2022 at a stroke center. Patients were 30 to 70 years of age and had a hematoma volume >15 cm ³ and National Institutes of Health Stroke Scale score >1. The patients underwent imaging 3×: within 12 to 24 (T1), 36 to 48 (T2), and 60 to 72 (T3) hours of last seen well on a 3T magnetic resonance imaging system. Three-dimensional anatomic, multigradient echo and 2-dimensional diffusion tensor images were obtained. Hematoma and edema volumes were calculated, and the distribution of coagulation was measured by dynamic changes in the susceptibilities and fractional anisotropy within the hematoma.
RESULTS
Using a coagulated blood phantom, we demonstrated a linear relationship between the percentage coagulation and susceptibility (R ² =0.91) with a positive red blood cell stain of the clot. The quantitative susceptibility maps showed a significant increase in hematoma susceptibility (T1, 0.29±0.04 parts per millions; T2, 0.36±0.04 parts per millions; T3, 0.45±0.04 parts per millions; P <0.0001). A concomitant increase in fractional anisotropy was also observed with time (T1, 0.40±0.02; T2, 0.45±0.02; T3, 0.47±0.02; P <0.05).
CONCLUSIONS
This quantitative neuroimaging study of coagulation within the hematoma has the potential to improve patient management, such as safe resumption of anticoagulants, the need for reversal agents, the administration of alteplase to resolve the clot, and the need for surgery.
... Therefore, strategies targeting this early phase of Oxidative Medicine and Cellular Longevity In our study, we also observed that baseline hematoma volume was independently associated with early PHE expansion. From a pathophysiological standpoint, the components of the hematoma may influence PHE evolution [25][26][27][28]. Studies have also indicated that the surrogate markers of iron load such as the serum ferritin level and hematocrit are considered to be the relevant factors for edema formation in ICH [25][26][27]. ...
... From a pathophysiological standpoint, the components of the hematoma may influence PHE evolution [25][26][27][28]. Studies have also indicated that the surrogate markers of iron load such as the serum ferritin level and hematocrit are considered to be the relevant factors for edema formation in ICH [25][26][27]. After erythrocyte lysis, the iron concentration in the brain could reach as high as 10 mmol/L, causing the thrombin-induced brain edema [25]. ...
Objective:
To investigate the association between early perihematomal edema (PHE) expansion and functional outcome in patients with intracerebral hemorrhage (ICH).
Methods:
Patients with ICH who underwent initial computed tomography (CT) scans within 6 hours after the onset of symptoms and follow-up CT scans within 24 ± 12 hours were included. Absolute PHE increase was defined as the absolute increase in PHE volume from baseline to 24 hours. A receiver-operating characteristic (ROC) curve was generated to determine the cutoff value for early PHE expansion, which was operationally defined as an absolute increase in PHE volume of >6 mL. The outcome of interest was 3-month poor outcome defined as modified Rankin scale score of ≥4. A multivariable logistic regression procedure was used to assess the association between early PHE expansion and outcome after ICH.
Results:
In 233 patients with ICH, 89 (38.2%) patients had poor outcome at 3-month follow-up. Early PHE expansion was observed in 56 of 233 (24.0%) patients. Patients with early PHE expansion were more likely to have poor functional outcome than those without (43.8% vs. 11.8%, p < 0.001). After adjusting for age, admission systolic blood pressure, admission Glasgow Coma Scale score, baseline ICH volume and the presence of intraventricular hemorrhage, and time from onset to CT, early PHE expansion was associated with poor outcome (adjusted odds ratio, 4.25; 95% confidence interval, 1.70-10.60; p = 0.002).
Conclusions:
The early PHE expansion was not uncommon in patients with ICH and was correlated with poor outcome following ICH.
... Iron Overload Leads to Ferroptosis After Stroke Before the concept of ferroptosis is defined, people have already recognized that the accumulation of iron in the brain will contribute to secondary brain injury (Wu et al., 2003;Lou et al., 2009;Liu et al., 2019). Currently, iron overload is thought to be a critical cause to trigger ferroptosis after ischemic stroke owning to its role of increasing mitochondrial oxidative damage and infarct volume (Lipscomb et al., 1998;Chi et al., 2000;Castellanos et al., 2002). ...
Ferroptosis is a unique regulated cell death defined by the intracellular iron overload and distinct biological features compared with other well-known programmed cell death. Ferroptosis can be triggered by many causes including decreased expression of glutathione (GSH), inhibition of the function of glutathione-dependent peroxidase 4 (GPX4), and system x c – , all of which finally lead to the over-accumulation of lipid peroxides in the cell. Ferroptosis has been reported to play an important role in the pathophysiological process of various cancers. In recent years, much evidence also proved that ferroptosis is involved in the progress of cerebral stroke. In this review, we summarized the characteristics of ferroptosis and the potential relationship between ferroptosis and ischemic and hemorrhagic stroke, to provide new targets and ideas for the therapy of stroke.
... PBI is followed by SBI, which is also considered a devastating stage after ICH(Cordonnier et al., 2018;Mohammed Thangameeran et al., 2020). Evidence from preclinical and clinical studies suggests that the host immune response, release of thrombin and clot components (iron and heme), increased cytotoxicity, and inflammation may contribute to SBI after ICH(Aronowski & Zhao, 2011;Harukuni & Bhardwaj, 2006;Lou et al., 2009;Wasserman & Schlichter, 2007;Xiong et al., 2014). The intricate mechanisms, including related modes of cell deaths during SBI, have become the interest of the current topics. ...
Stroke is a disastrous neurological disease with high morbidity and mortality. The mechanism of the pathological process is extremely complicated and unclear. Although many basic studies have confirmed molecular mechanism of brain injury after stroke, these studies have not yet translated into treatment and clinical application. Ferroptosis is a form of cell death that is distinct from necrosis, apoptosis, and autophagy morphologically and biochemically and is characterized by iron‐dependent accumulation of lipid peroxides. Despite ferroptosis being first identified in cancer cells, it was recently revealed to also be a significant factor in the pathological process of stroke. A better understanding of ferroptosis in stroke may provide us with better therapeutic targets to treat this devastating disease. Here, we systematically summarized the current mechanism of ferroptosis and reviewed the current studies regarding the relationship between ferroptosis and stroke.
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... [1][2][3] Except the traditional dehydration drugs, many other drugs including oxygen free radical scavenger, calcium antagonist, thrombin inhibitors, complement inhibitors, aquaporin inhibitors etc. emerged depended on the pathogenesis of PHE. DFX as one of these new types of antihydropic drugs, exerts its function through chelating iron, which is released from ICH and related to PHE. [1,4,5] DFX has been proved effective in sustaining PHE and promoting hematoma absorption in many preliminary and clinical studies, but the treatment is controversial. At present, a single meta-analysis comprising animal model experiments and one clinical systematic review on deferoxamine treatment for ICH exist. ...
Background
Deferoxamine (DFX) is reckoned effective for treating intracerebral hematoma (ICH). However, its therapeutic effects remain controversial. Although one systematic review was conducted previously, the pooled data analysis could not be done owing to the limited studies included. In our study, we searched additional databases and included more studies to conduct a meta-analysis on the therapeutic effects of DFX considering hematoma absorption, relative edema volume, and neurological prognosis of ICH patients.
Methods
We searched Embase, Cochrane Library, PubMed, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Database, Chinese Biomedical Literature Database, and Clinical Trials.gov in May 2020 for studies on DFX for ICH patients. The quality of randomized controlled trials (RCTs) was assessed using the Cochrane Risk of Bias Tool and that of cohort studies using the Newcastle–Ottawa Scale. Random-effect and fixed-effect models were used for pooled analysis.
Results
After screening 1820 articles, 3 cohort studies, and 5 RCTs were included. We found that DFX exhibits no therapeutic effects with regard to hematoma absorption on the days 7 and 14 after onset. DFX could suppress edema expansion on days 3 and 7 after onset,however, there was a difference on day 14. Regarding neurological outcomes, DFX did not lead to better outcomes after both one week and 15 days when evaluated using the National Institute of Health Stroke Scale and after 3 months using the modified Rankin scale. There was no obvious advantage despite including an unpublished study on using high dose DFX to evaluate neurological outcomes 3 months after onset.
Conclusions
DFX could impede edema expansion on days 3 and 7 after onset without promoting hematoma absorption, neither improving neurological outcomes.
... ROS can cause over activation of microglia after ICH. Excessive ROS after ICH was observed in patients as well as in animal models and was associated with secondary brain injury [36,37]. But so far, The antioxidants failed in the multi-center clinical trial of intracerebral haemorrhage [6,7]. ...
... Our results showed that inhibition of mitochondrial ROS can reduce the activation of M1 microglia and promote the polarization of M2 microglia both in vivo and in vitro. Acute and severe iron overload is observed in the brain tissues of patients and experimental animals after ICH and is closely related to secondary brain injury [37,48]. An increase in iron reserves is related to a variety of nervous system diseases by affecting the production of inflammation and reactive oxygen species [49]. ...
Microglial phenotype plays an important role in secondary injury after intracerebral haemorrhage (ICH), with M1 microglia promoting inflammatory injury and M2 microglia inhibiting neuroinflammation and promoting haematoma absorption. However, there is no effective intervention for regulating the phenotypic transformation of microglia after ICH. This study aimed to elucidate the protective effect of MitoQ, a selective mitochondrial ROS antioxidant, against microglial M1 state polarization and secondary brain injury. The in vivo data showed that MitoQ attenuated neurological deficits and decreased inflammation, oedema and haematoma volume after ICH. In addition, MitoQ decreased the expression of M1 markers and increased the expression of M2 markers both in vivo and in vitro after ICH. Mechanistically, MitoQ blocked overproduction of mitochondrial ROS and activation of the NLRP3 inflammasome in FeCl2-treated microglia. Moreover, NLRP3 siRNA shifted FeCl2-treated microglia from the M1 to the M2 cells, revealing that MitoQ-induce polarization states may be mediated by the mitochondrial ROS/NLRP-3 pathway. In summary, MitoQ alleviates secondary brain injury and accelerates haematoma resolution by shifting microglia towards the M2 phenotype after ICH.
... The early stage of cerebral edema occurs in the rst few hours after ICH, which involves hydrostatic pressure induced by formation of hematoma and retraction of clot, the second phase, caused by production of thrombin and activation of the coagulation cascade, occurs within the rst 24 hours, and the delayed stage involves in red blood cells hemolysis and hemoglobin-induced toxicity [33,34]. The sizes of perihematoma edema have also been related to several factors such as the level of serum ferritin and increased matrix metalloproteinase-9 activity, which is an important enzyme for the blood brain barrier remodeling and perihematoma edema development [35][36][37][38]. ...
Background: Obesity is one of the major risk factors of intracerebral hemorrhage (ICH). Neck circumference (NC) is an indicator of obesity, and little is known about the role of NC in patients with ICH. This study aimed to assess the association between NC and functional outcome in ICH patients.
Methods: We prospectively analyzed data of ICH patients who received treatment at our institution from January 2018 to November 2019. Patients were categorized as two groups according to 180-day Modified Rankin Scale (MRS) score. Univariate and multivariate analyses were performed to assess whether NC was associated with poor outcome in ICH patients. Receiver operating characteristic (ROC) curve analysis was performed to manifest the significance of NC in predicting the functional outcome of ICH patients.
Results: A total of 312 patients were enrolled in our study. Multivariate logistic regression analysis indicated that NC was an independent predictor of 180-day poor functional outcome (odds ratio [OR] = 1.205, 95% confidence interval [CI]: 1.075-1.350, p = 0.001). ROC analysis revealed that NC could predict poor functional outcome at 6 months.
Conclusion: NC is an independent predictor of unfavorable functional outcome at 6 months in ICH patients.
... Iron-mediated free radical generation and oxidative damage lead to neuronal injury and perihematomal edema formation in cases of cerebral hemorrhage. 23,24 Serum ferritin can quantify the body iron stores more reliably than other iron indices such as serum iron, transferrin, total iron-binding capacity as the latter ones carried greater biological variabilities than ferritin. 25 Xie et al established serum ferritin to be an independent predictor of long-term functional outcome in neurocritically ill patients amidst all other iron indices. ...
Background Acute hemorrhagic stroke (AHS) resulting from intracerebral hemorrhage (ICH) is a rampant neurological disorder with devastating consequences, particularly in Indians. Recently, serum ferritin levels have been related to adverse car-diovascular and stroke outcomes. We aimed to evaluate the prognostic utility of serum ferritin in AHS. Materials and Methods Admission serum ferritin levels were estimated in 50 AHS patients with primary supratentorial hemorrhage. Study subjects were categorized based on their prognostic scores in modified Rankin scale (mRS) assessment. Ferritin levels were compared across the study groups, correlated with mRS and other ICH severity indicators. Results Serum ferritin and other ICH severity indices such as Glasgow coma scale (GCS) and ICH volume were significantly altered in the mRS groups by the end of 7th and 30th days of hospitalization. Elevated ferritin levels, ICH volume together with decreased GCS, characterized the groups with adverse prognosis. Serum ferri-tin moderately correlated with GCS (r =-0.643), ICH volume (r = 0.562), and had significantly higher correlations with long-term prognostic scores of 7th day mRS (r = 0.802) and 30th day mRS (r = 0.916). Conclusion Elevated admission serum ferritin levels indicate poor AHS short-term and long-term outcomes, thereby making serum ferritin a possible prognostic index for the same. Abstract Keywords ► serum ferritin ► acute hemorrhagic stroke ► prognosis ► modified Rankin scale
... [40]. Iron overload after ICH was observed in patients as well as in animal models and was associated with excessive ROS production around the hematoma [41,42]. Although clinical studies of the nonselective reactive oxygen scavenger edaravone have failed [11,12], interventions that selectively target mitochondrial ROS or specific oxidants are still promising treatments for ICH. ...
White matter injury (WMI) is an important cause of high disability after intracerebral haemorrhage (ICH). It is widely accepted that reactive oxygen species (ROS) contributes to WMI, but there is still no evidence-based treatment. Here, mitoquinone (MitoQ), a newly developed selective mitochondrial ROS scavenger, was used to test its neuroprotective potential. The data showed that MitoQ attenuated motor function deficits and motor-evoked potential (MEP) latency prolongation. Further research found that MitoQ blunted the loss of oligodendrocytes and oligodendrocyte precursor cells, therefore reduced demyelination and axon swelling after ICH. In the in vitro experiments, MitoQ, but not the nonselective antioxidant, almost completely attenuated the iron-induced membrane potential decrease and cell death. Mechanistically, MitoQ blocked the ATP deletion and mitochondrial ROS overproduction. The present study demonstrates that the selective mitochondrial ROS scavenger MitoQ may improve the efficacy of antioxidant treatment of ICH by white matter injury alleviation.
