Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

2012 ◽  
Vol 32 (4) ◽  
pp. E8 ◽  
Author(s):  
Ranjith Babu ◽  
Jacob H. Bagley ◽  
Chunhui Di ◽  
Allan H. Friedman ◽  
Cory Adamson
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Mass Effect ◽  
Thrombin Inhibitors ◽  
Hematoma Expansion ◽  
Secondary Brain Injury ◽  
Antiinflammatory Drugs ◽  
Primary Hemorrhage

Intracerebral hemorrhage (ICH) is a subtype of stoke that may cause significant morbidity and mortality. Brain injury due to ICH initially occurs within the first few hours as a result of mass effect due to hematoma formation. However, there is increasing interest in the mechanisms of secondary brain injury as many patients continue to deteriorate clinically despite no signs of rehemorrhage or hematoma expansion. This continued insult after primary hemorrhage is believed to be mediated by the cytotoxic, excitotoxic, oxidative, and inflammatory effects of intraparenchymal blood. The main factors responsible for this injury are thrombin and erythrocyte contents such as hemoglobin. Therapies including thrombin inhibitors, N-methyl-D-aspartate antagonists, chelators to bind free iron, and antiinflammatory drugs are currently under investigation for reducing this secondary brain injury. This review will discuss the molecular mechanisms of brain injury as a result of intraparenchymal blood, potential targets for therapeutic intervention, and treatment strategies currently in development.

scholarly journals Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury

2013 ◽  
Vol 34 (5) ◽  
pp. E9 ◽  
Author(s):  
Praveen K. Belur ◽  
Jason J. Chang ◽  
Shuhan He ◽  
Benjamin A. Emanuel ◽  
William J. Mack
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Mass Effect ◽  
Therapeutic Strategies ◽  
Experimental Models ◽  
Thrombin Inhibitors ◽  
Hematoma Expansion ◽  
Secondary Brain Injury ◽  
Limited Efficacy ◽  
Experimental Therapies

Intracerebral hemorrhage (ICH) is associated with a higher degree of morbidity and mortality than other stroke subtypes. Despite this burden, currently approved treatments have demonstrated limited efficacy. To date, therapeutic strategies have principally targeted hematoma expansion and resultant mass effect. However, secondary mechanisms of brain injury are believed to be critical effectors of cell death and neurological outcome following ICH. This article reviews the pathophysiology of secondary brain injury relevant to ICH, examines pertinent experimental models, and highlights emerging therapeutic strategies. Treatment paradigms discussed include thrombin inhibitors, deferoxamine, minocycline, statins, granulocyte-colony stimulating factors, and therapeutic hypothermia. Despite promising experimental and preliminary human data, further studies are warranted prior to effective clinical translation.

Novel Synthetic and Natural Therapies for Traumatic Brain Injury

2021 ◽  
Vol 19 ◽  
Author(s):  
Denise Battaglini ◽  
Dorota Siwicka-Gieroba ◽  
Patricia RM Rocco ◽  
Fernanda Ferreira Cruz ◽  
Pedro Leme Silva ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Damage ◽  
Molecular Mechanisms ◽  
Antioxidant Properties ◽  
Secondary Brain Injury ◽  
Specific Recommendation ◽  
Novel Therapies ◽  
Secondary Brain Damage ◽  
Late Treatment

: Traumatic brain injury (TBI) is a major cause of disability and death worldwide. The initial mechanical insult results in tissue and vascular disruption with hemorrhages and cellular necrosis that is followed by a dynamic secondary brain damage that presumably results in additional destruction of the brain. In order to minimize deleterious consequences of the secondary brain damage-such as inflammation, bleeding or reduced oxygen supply. The old concept of the -staircase approach- has been updated in recent years by most guidelines and should be followed as it is considered the only validated approach for the treatment of TBI. Besides, a variety of novel therapies have been proposed as neuroprotectants. The molecular mechanisms of each drug involved in inhibition of secondary brain injury can result as potential target for the early and late treatment of TBI. However, no specific recommendation is available on their use in clinical setting. The administration of both synthetic and natural compounds, which act on specific pathways involved in the destructive processes after TBI, even if usually employed for the treatment of other diseases, can show potential benefits. This review represents a massive effort towards current and novel therapies for TBI that have been investigated in both pre-clinical and clinical settings. This review aims to summarize the advancement in therapeutic strategies basing on specific and distinct -target of therapies-: brain edema, ICP control, neuronal activity and plasticity, anti-inflammatory and immunomodulatory effects, cerebral autoregulation, antioxidant properties, and future perspectives with the adoption of mesenchymal stromal cells.

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 Acrolein Aggravates Secondary Brain Injury After Intracerebral Hemorrhage Through Drp1-Mediated Mitochondrial Oxidative Damage in Mice

2020 ◽  
Vol 36 (10) ◽  
pp. 1158-1170
Author(s):  
Xun Wu ◽  
Wenxing Cui ◽  
Wei Guo ◽  
Haixiao Liu ◽  
Jianing Luo ◽  
...  
Keyword(s):  
Brain Injury ◽  
Oxidative Damage ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Mitochondrial Fission ◽  
Secondary Brain Injury ◽  
Functional Deficits ◽  
Highly Active ◽  
Neural Apoptosis ◽  
Mitochondrial Oxidative Damage

Abstract Clinical advances in the treatment of intracranial hemorrhage (ICH) are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury. Acrolein is a highly active unsaturated aldehyde which has been implicated in many nervous system diseases. Our results indicated a significant increase in the level of acrolein after ICH in mouse brain. In primary neurons, acrolein induced an increase in mitochondrial fragmentation, loss of mitochondrial membrane potential, generation of reactive oxidative species, and release of mitochondrial cytochrome c. Mechanistically, acrolein facilitated the translocation of dynamin-related protein1 (Drp1) from the cytoplasm onto the mitochondrial membrane and led to excessive mitochondrial fission. Further studies found that treatment with hydralazine (an acrolein scavenger) significantly reversed Drp1 translocation and the morphological damage of mitochondria after ICH. In parallel, the neural apoptosis, brain edema, and neurological functional deficits induced by ICH were also remarkably alleviated. In conclusion, our results identify acrolein as an important contributor to the secondary brain injury following ICH. Meanwhile, we uncovered a novel mechanism by which Drp1-mediated mitochondrial oxidative damage is involved in acrolein-induced brain injury.

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 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.

Inhibition of EPAC2 Attenuates Intracerebral Hemorrhage-Induced Secondary Brain Injury via the p38/BIM/Caspase-3 Pathway

2019 ◽  
Vol 67 (3) ◽  
pp. 353-363 ◽  
Author(s):  
Yan Zhuang ◽  
Hui Xu ◽  
Seidu A. Richard ◽  
Jie Cao ◽  
Haiying Li ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Caspase 3 ◽  
Secondary Brain Injury
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