scholarly journals Intrathecal and systemic alterations of L-arginine metabolism in patients after intracerebral hemorrhage

2021 ◽  
pp. 0271678X2098321
Author(s):  
Marius M Mader ◽  
Rainer Böger ◽  
Daniel Appel ◽  
Edzard Schwedhelm ◽  
Munif Haddad ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Vascular Diseases ◽  
Secondary Brain Injury ◽  
Arginine Metabolism ◽  
Metabolizing Enzymes ◽  
Liquid Chromatography Tandem Mass ◽  
Elevated Activity ◽  
Nos Inhibitor ◽  
Arginine Concentration ◽  
Observation Period

Alterations in the concentration of nitric oxide (NO) and L-arginine metabolites have been associated with the pathophysiology of different vascular diseases. Here, we describe striking changes in L-arginine metabolism after hemorrhagic stroke. Blood and cerebrospinal fluid (CSF) samples of patients with intracerebral hemorrhage (ICH) and/or intraventricular hemorrhage were collected over a ten-day period. Liquid chromatography-tandem mass spectrometry was used to quantify key substrates and products of L-arginine metabolizing enzymes as well as asymmetric (ADMA) and symmetric dimethylarginine (SDMA). Changes in the plasma were limited to early reductions in L-ornithine, L-lysine, and L-citrulline concentrations. Intrathecally, we observed signs of early NO synthase (NOS) upregulation followed by a decrease back to baseline accompanied by a rise in the level of its endogenous NOS-inhibitor ADMA. SDMA demonstrated increased levels throughout the observation period. For arginase, a pattern of persistently elevated activity was measured and arginine:glycine amidinotransferase (AGAT) appeared to be reduced in its activity at later time points. An early reduction in CSF L-arginine concentration was an independent risk factor for poor outcome. Together, these findings further elucidate pathophysiological mechanisms after ICH potentially involved in secondary brain injury and may reveal novel therapeutic targets.

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.

scholarly journals Arginine metabolism and nitric oxide turnover in the ZSF1 animal model for heart failure with preserved ejection fraction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Petra Büttner ◽  
Sarah Werner ◽  
Svetlana Baskal ◽  
Dimitrios Tsikas ◽  
Volker Adams ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Inflammatory Cells ◽  
No Synthase ◽  
Preserved Ejection Fraction ◽  
Arginine Metabolism ◽  
Metabolizing Enzymes ◽  
Arginase 1 ◽  
Liver And Kidney

AbstractEndothelial dysfunction and altered nitric oxide (NO) metabolism are considered causal factors in heart failure with preserved ejection fraction (HFpEF). NO synthase activity depends on the availability of arginine and its derivatives. Thus, we analyzed arginine, associated metabolites, arginine-metabolizing enzymes and NO turnover in 20-week-old female healthy lean (L-ZSF1) and obese ZSF1 rats (O-ZSF1) with HFpEF. Serum, urine and lysates of liver, kidney and heart were analyzed. There were significantly lower lysine (− 28%), arginine (− 31%), homoarginine (− 72%) and nitrite (− 32%) levels in serum of O-ZSF1 rats. Ornithine (+ 60%) and citrulline (+ 20%) levels were higher. Similar results were found in the heart. Expression of arginine consuming enzymes in liver and kidney was unchanged. Instead, we observed a 5.8-fold higher arginase 1 expression, presumably of granulocyte origin, in serum and > fourfold increased cardiac macrophage invasion in O-ZSF1. We conclude that inflammatory cells in blood and heart consume arginine and probably homoarginine via arginase 1 and inducible NO synthase and release ornithine and citrulline. In combination with evidence for decreased NO turnover in O-ZSF1 rats, we assume lower arginine bioavailability to endothelial NO synthase.

Abstract TP376: Heme Oxygenase-1 is Essential for Hematoma Clearance After Intracerebral Hemorrhage

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Liyan Zhang ◽  
Xiurong Zhao ◽  
Guanghua Sun ◽  
Jaroslaw Aronowski
Keyword(s):  
Intracerebral Hemorrhage ◽  
Rat Brain ◽  
Heme Oxygenase ◽  
Functional Recovery ◽  
Protoporphyrin Ix ◽  
Neuronal Injury ◽  
Neurological Deficits ◽  
Sublethal Dose ◽  
Heme Oxygenase 1 ◽  
Secondary Brain Injury

Background: After intracerebral hemorrhage (ICH), the red blood cells (RBC) and their hemolytic products within brain hematoma trigger adverse biochemical events, leading to secondary brain injury and neurological deficits. Thus, efficient removal of hematoma components is essential for achieving inflammation resolution and functional recovery. The inducible heme-oxygenase (HO-1) is a key rate-limiting enzyme that catabolizes heme into iron, CO, and biliverdin. The present study investigated the role of HO-1 in microglia/macrophages (MΦ)-mediated phagocytosis of RBC; and also assessed the spatial and temporal expression of HO-1 in ICH-affected brain, as well as its possible role in the clearance of hematoma components following ICH modeled in rodents. Methods and Results: First, we employed the rat brain MΦ. Upon exposing to RBC, MΦ phagocytize RBC; and HO-1 was induced during this process. Co-incubating tin-protoporphyrin IX (SnPP, a competitive HO-1 inhibitor) with RBC significantly delayed RBC internalization by MΦ. Removal of SnPP from the culture medium led to a rapid recovery of MΦ’s phagocytic function, suggesting that SnPP-induced inhibition is a reversible process. Subjecting neuron-microglia co-cultures to RBC plus sublethal dose of oxygen-deprivation (an ICH-like insult) triggered neuronal injury, as assessed using neurofilament degradation assay and loss of NeuN-positive cells; and addition of SnPP further aggravated the neuronal injury. Additional studies showed that after ICH, HO-1 is up-regulated in hematoma-affected rat brain tissues starting from 6h, reaching the maximum level at 3-7days, and persisting for at least 10 days after ICH. Double immunohistochemistry of HO-1 and brain cell markers shows that the most HO-1-positive cells are Iba1-positive MΦ. Administration of SnPP for 7 days, (7.5 mg/kg, ip, twice a day) delayed hematoma clearance by 27.8% and significantly impaired the functional recovery, as measured 7 days after ICH. Histological analyses showed that there are more TUNEL-positive neurons in the hematoma-affected brain tissue in SnPP-treated mouse brains. Conclusion: Our study suggests that HO-1 is essential for phagocytosis of RBC by MΦ, which is critical for endogenous clearance of hematoma after ICH.

Abstract P423: Race and Ethnicity Influence Perihematomal Edema Volume in Supratentorial Intracerebral Hemorrhage

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Julian N Acosta ◽  
Yasheng Chen ◽  
Cameron Both ◽  
Audrey C Leasure ◽  
Fernando Testai ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Race And Ethnicity ◽  
Learning Algorithm ◽  
Multivariable Analysis ◽  
Secondary Brain Injury ◽  
Racial Groups ◽  
Deep Learning Algorithm ◽  
Perihematomal Edema ◽  
Study Participants ◽  
Racial Ethnic

Introduction: Perihematomal Edema (PHE) is a neuroimaging biomarker of secondary brain injury in patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH). There are limited data on racial/ethnic differences in the development of PHE. This dearth of data is partially driven by the time-consuming process of manually segmenting PHE. Leveraging a validated automated pipeline for PHE segmentation, we evaluated whether race and ethnicity influence baseline PHE volume in patients with ICH. Methods: The Ethnic/Racial Variations in Intracerebral Hemorrhage (ERICH) study is a prospective, multicenter study of ICH that recruited 1,000 adult participants from each of three racial/ethnic groups (non-Hispanic White, non-Hispanic Black, and Hispanic). We applied a previously validated deep learning algorithm to automatically determine PHE volumes on baseline CTs in these study participants. Quality control procedures were used to include only sufficiently accurate PHE measurements. Linear regression was used to identify factors associated with log-transformed PHE volume and to identify differences across Ethnic/Racial groups. Results: Our imaging pipeline provided good quality baseline PHE measurements on 2,008 out of 3,000 ERICH study participants. After excluding infratentorial hemorrhages (273) and those with missing or null baseline ICH volume (49), 1,686 remained for analysis (median age 59 [IQR 51-71], 687 [41%] female sex). Median PHE volume was 12.0 (IQR 4.8-27.1) for whites, 11.9 (IQR 4.5-26.1) for Hispanics and 8.3 (IQR 3.0-19.2) for blacks. Compared to Blacks, Hispanics (beta 0.22; 95%CI 0.11-0.32; p<0.001) and Whites (beta 0.20; 95%CI 0.07-0.33; p=0.003) had higher baseline PHE volumes, in multivariable analysis adjusting for age, sex, ICH location, log-baseline ICH volume, log-baseline intraventricular volume, and systolic blood pressure on admission. Conclusion: Race and ethnicity influence the volume of baseline PHE. Further studies are needed to validate our results and investigate the biological underpinnings of this difference.

RAB7L1 Participates in Secondary Brain Injury Induced by Experimental Intracerebral Hemorrhage in Rats

2020 ◽  
Vol 71 (1) ◽  
pp. 9-18
Author(s):  
Xiaoxing Tan ◽  
Yuchong Wei ◽  
Jie Cao ◽  
Degang Wu ◽  
Niansheng Lai ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Secondary Brain Injury

scholarly journals Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1326 ◽  
Author(s):  
Hock-Kean Liew ◽  
Wei-Fen Hu ◽  
Peter Bor-Chian Lin ◽  
Po-Kai Wang ◽  
Andy Po-Yi Tsai ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Er Stress ◽  
Inflammatory Cytokines ◽  
Proteasome Inhibitor ◽  
Neuronal Cell ◽  
Neurological Deficits ◽  
Critical Event ◽  
Secondary Brain Injury ◽  
Proteasome Inhibitor Mg132 ◽  
Pro Inflammatory Cytokines

Background: Neuroinflammation is a hallmark in intracerebral hemorrhage (ICH) that induces secondary brain injury, leading to neuronal cell death. ER stress-triggered apoptosis and proteostasis disruption caused neuroinflammation to play an important role in various neurological disorders. The consequences of ER stress and proteostasis disruption have rarely been studied during the course of ICH development. Methods: ICH was induced by collagenase VII-S intrastriatal infusion. Animals were sacrificed at 0, 3, 6, 24, and 72 h post-ICH. Rats were determined for body weight changes, hematoma volume, and neurological deficits. Brain tissues were harvested for molecular signaling analysis either for ELISA, immunoblotting, immunoprecipitation, RT-qPCR, protein aggregation, or for histological examination. A non-selective proteasome inhibitor, MG132, was administered into the right striatum three hours prior to ICH induction. Results: ICH-induced acute proteasome over-activation caused the early degradation of the endoplasmic reticulum (ER) chaperone GRP78 and IκB protein. These exacerbations were accompanied by the elevation of pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP) and pro-inflammatory cytokines expression via nuclear factor-kappa B (NF-κB) signal activation. Pre-treatment with proteasome inhibitor MG132 significantly ameliorated the ICH-induced ER stress/proteostasis disruption, pro-inflammatory cytokines, neuronal cells apoptosis, and neurological deficits. Conclusions: ICH induced rapid proteasome over-activation, leading to an exaggeration of the ER stress/proteostasis disruption, and neuroinflammation might be a critical event in acute ICH pathology.

scholarly journals Changes in Transporters and Metabolizing Enzymes in the Livers of Rats with Bile Duct Ligation

2019 ◽  
Vol 22 ◽  
pp. 457-465 ◽  
Author(s):  
Atsushi Kawase ◽  
Akira Kazaoka ◽  
Rei Yamamoto ◽  
Risa Minakata ◽  
Hiroaki Shimada ◽  
...  
Keyword(s):  
Bile Duct ◽  
Membrane Proteins ◽  
Nuclear Receptors ◽  
Bile Duct Ligation ◽  
Scaffold Proteins ◽  
Mrna Levels ◽  
Metabolizing Enzymes ◽  
Protein Levels ◽  
Duct Ligation ◽  
Liquid Chromatography Tandem Mass

Purpose: Bile duct ligation (BDL) in experimental animals is widely used as an animal model of liver cholestasis and fibrosis. The transcriptional process and plasma membrane localization of transporters are regulated by nuclear receptors and scaffold proteins, respectively. However, the detailed changes of these factors in the livers of BDL rats remain unclear. To clarify the effects of BDL on the levels of transporters and metabolizing enzymes, nuclear receptors, and scaffold proteins, we investigated changes in mRNA and protein levels of livers from BDL rats. Methods: Membrane proteins and microsomes were prepared from rats with BDL. The mRNA levels of transporters and nuclear receptors in livers of control and BDL rats were examined by real-time reverse transcription polymerase chain reaction. The protein levels of transporters, metabolizing enzymes and scaffold proteins in membrane proteins and microsomes were determined by liquid chromatography-tandem mass spectrometry-based targeted proteomics. Results: Mdr1a mRNA was significantly decreased at 1 and 2 weeks of BDL. The mRNA levels of MRP2 were significantly decreased. The mRNA levels of nuclear receptors were significantly decreased in livers of 1-week BDL rats. The protein levels of P-gp were significantly increased by BDL. Regarding scaffold proteins, the protein levels of ezrin, moesin and EBP50 were significantly decreased at 2 weeks of BDL. The protein levels of radixin were significantly increased at 1 week of BDL. In 1-week BDL rats, the protein levels of metabolizing enzymes such as CYP and UGT were significantly decreased. Conclusions: This study reports the comprehensive changes of transporters, metabolizing enzymes, nuclear receptors, and ezrin/radixin/moesin proteins in the livers of BDL rats. The expression levels of nuclear receptors and radixin that regulate the transcription and localization of CYP and/or transporters were decreased by BDL.

scholarly journals Association between neutrophil to lymphocyte ratio and blood glucose level at admission in patients with spontaneous intracerebral hemorrhage

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Fan Zhang ◽  
Yanming Ren ◽  
Wei Fu ◽  
Yuelong Wang ◽  
Juan Qian ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Blood Glucose ◽  
Intracerebral Hemorrhage ◽  
Blood Glucose Level ◽  
Glucose Level ◽  
Inflammatory Responses ◽  
Neutrophil To Lymphocyte Ratio ◽  
Secondary Brain Injury ◽  
Imaging Features ◽  
Lymphocyte Ratio

Abstract Previous studies indicated that both inflammatory responses and hyperglycemia are involved in the similar pathophysiological mechanisms after onset of intracerebral hemorrhage (ICH). However the relationship between hyperglycemia and inflammation remains unknown. We aim to evaluate the associations of hyperglycemia with inflammation and neutrophil to lymphocyte ratio (NLR) in patients with ICH. Patients with acute ICH were retrospectively enrolled. Clinical characteristics and imaging features were obtained. The associations between outcome and laboratory biomarkers were assessed by multivariable logistic regression analysis. Spearman analysis and multiple linear regression analysis were performed to estimate the association of NLR and serum glucose. 175 patients were enrolled. Poor outcome occurred in 86 patients at 30 days. Elevated blood glucose level (BGL) and NLR were strongly associated with outcome in patients with ICH. Moreover, combined NLR-BGL exhibited a better predictive accuracy compared with the peripheral leukocyte counts. Furthermore, there was a robust association between BGL and NLR. We first demonstrated both of NLR and BGL were independently associated with each other. Our results indicate that inflammatory responses and the pathological process of hyperglycemia may influence each other by several complex pathological mechanisms and have a mutual promoting effect to secondary brain injury.

scholarly journals Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124

2020 ◽  
pp. 0271678X2091686 ◽  
Author(s):  
Fang Shen ◽  
Xiang Xu ◽  
Zhengquan Yu ◽  
Haiying Li ◽  
Haitao Shen ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Protein Level ◽  
Rna Binding ◽  
Neuronal Degeneration ◽  
Binding Protein ◽  
Neurological Diseases ◽  
Rna Binding Protein ◽  
Micro Rna ◽  
Secondary Brain Injury

RNA-binding protein fox-1 homolog 1 (Rbfox-1), an RNA-binding protein in neurons, is thought to be associated with many neurological diseases. To date, the mechanism on which Rbfox-1 worsens secondary cell death in ICH remains poorly understood. In this study, we aimed to explore the role of Rbfox-1 in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and to identify its underlying mechanisms. We found that the expression of Rbfox-1 in neurons was significantly increased after ICH, which was accompanied by increases in the binding of Rbfox-1 to Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) mRNA and the protein level of CaMKIIα. In addition, when exposed to exogenous upregulation or downregulation of Rbfox-1, the protein level of CaMKIIα showed a concomitant trend in brain tissue, which further suggested that CaMKIIα is a downstream-target protein of Rbfox-1. The upregulation of both proteins caused intracellular-Ca2+ overload and neuronal degeneration, which exacerbated brain damage. Furthermore, we found that Rbfox-1 promoted the expression of CaMKIIα via blocking the binding of micro-RNA-124 to CaMKIIα mRNA. Thus, Rbfox-1 is expected to be a promising therapeutic target for SBI after ICH.

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