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    Treatment with TO901317, a synthetic liver X receptor agonist, reduces brain damage and attenuates neuroinflammation in experimental intracerebral hemorrhage. Wu Chun-Hu,Chen Chien-Cheng,Lai Chai-You,Hung Tai-Ho,Lin Chao-Chang,Chao Min,Chen Szu-Fu Journal of neuroinflammation BACKGROUND:Intracerebral hemorrhage (ICH) induces a series of inflammatory processes that contribute to neuronal damage and neurological deterioration. Liver X receptors (LXRs) are nuclear receptors that negatively regulate transcriptional processes involved in inflammatory responses, but their role in the pathology following ICH remains unclear. The present study investigated the neuroprotective effects and anti-inflammatory actions of TO901317, a synthetic LXR agonist, in a model of collagenase-induced ICH and in microglial cultures. METHODS:Mice subjected to collagenase-induced ICH injury were injected with either TO901317 (30 mg/kg) or vehicle 10 min after ICH and subsequently daily for 2 days. Behavioral studies, histology analysis, and assessments of hematoma volumes, brain water content, and blood-brain barrier (BBB) permeability were performed. The protein expression of LXR-α, LXR-β, ATP binding cassette transporter-1 (ABCA-1), and inflammatory molecules was analyzed. The anti-inflammatory mechanism of TO901317 was investigated in cultured microglia that were stimulated with either lipopolysaccharide (LPS) or thrombin. RESULTS:ICH induced an increase in LXR-α protein levels in the hemorrhagic hemisphere at 6 h whereas LXR-β expression remained unaffected. Both LXR-α and LXR-β were expressed in neurons and microglia in the peri-ICH region and but rarely in astrocytes. TO901317 significantly attenuated functional deficits and brain damage up to 28 days post-ICH. TO901317 also reduced neuronal death, BBB disruption, and brain edema at day 4 post-ICH. These changes were associated with marked reductions in microglial activation, neutrophil infiltration, and expression levels of inflammatory mediators at 4 and 7 days. However, TO901317 had no effect on matrix metalloproteinase-9 activity. In BV2 microglial cultures, TO901317 attenuated LPS- and thrombin-stimulated nitric oxide production and reduced LPS-induced p38, JNK, MAPK, and nuclear factor-kappa B (NF-κB) signaling. Moreover, delaying administration of TO901317 to 3 h post-ICH reduced brain tissue damage and neuronal death. CONCLUSIONS:Our results suggest that enhancing LXR activation may provide a potential therapy for ICH by modulating the cytotoxic functions of microglia. 10.1186/s12974-016-0524-8
    Ergosta-7,9(11),22-trien-3β-ol Alleviates Intracerebral Hemorrhage-Induced Brain Injury and BV-2 Microglial Activation. Hsueh Po-Jen,Wang Mong-Heng,Hsiao Che-Jen,Chen Chih-Kuang,Lin Fan-Li,Huang Shu-Hsien,Yen Jing-Lun,Tsai Ping-Huei,Kuo Yueh-Hsiung,Hsiao George Molecules (Basel, Switzerland) Intracerebral hemorrhage (ICH) is a devastating neurological disorder characterized by an exacerbation of neuroinflammation and neuronal injury, for which few effective therapies are available at present. Inhibition of excessive neuroglial activation has been reported to alleviate ICH-related brain injuries. In the present study, the anti-ICH activity and microglial mechanism of ergosta-7,9(11),22-trien-3β-ol (EK100), a bioactive ingredient from Asian medicinal herb , were evaluated. Post-treatment of EK100 significantly attenuated neurobehavioral deficit and MRI-related brain lesion in the mice model of collagenase-induced ICH. Additionally, EK100 alleviated the inducible expression of cyclooxygenase (COX)-2 and the activity of matrix metalloproteinase (MMP)-9 in the ipsilateral brain regions. Consistently, it was shown that EK100 concentration-dependently inhibited the expression of COX-2 protein in Toll-like receptor (TLR)-4 activator lipopolysaccharide (LPS)-activated microglial BV-2 and primary microglial cells. Furthermore, the production of microglial prostaglandin E and reactive oxygen species were attenuated by EK100. EK100 also attenuated the induction of astrocytic MMP-9 activation. Among several signaling pathways, EK100 significantly and concentration-dependently inhibited activation of c-Jun N-terminal kinase (JNK) MAPK in LPS-activated microglial BV-2 cells. Consistently, ipsilateral JNK activation was markedly inhibited by post-ICH-treated EK100 in vivo. In conclusion, EK100 exerted the inhibitory actions on microglial JNK activation, and attenuated brain COX-2 expression, MMP-9 activation, and brain injuries in the mice ICH model. Thus, EK100 may be proposed and employed as a potential therapeutic agent for ICH. 10.3390/molecules26102970
    Baicalin mitigates cognitive impairment and protects neurons from microglia-mediated neuroinflammation via suppressing NLRP3 inflammasomes and TLR4/NF-κB signaling pathway. Jin Xin,Liu Ming-Yan,Zhang Dong-Fang,Zhong Xin,Du Ke,Qian Ping,Yao Wei-Fan,Gao Hua,Wei Min-Jie CNS neuroscience & therapeutics AIMS:Baicalin (BAI), a flavonoid compound isolated from the root of Scutellaria baicalensis Georgi, has been established to have potent anti-inflammation and neuroprotective properties; however, its effects during Alzheimer's disease (AD) treatment have not been well studied. This study aimed to investigate the effects of BAI pretreatment on cognitive impairment and neuronal protection against microglia-induced neuroinflammation and to explore the mechanisms underlying its anti-inflammation effects. METHODS:To determine whether BAI plays a positive role in ameliorating the memory and cognition deficits in APP (amyloid beta precursor protein)/PS1 (presenilin-1) mice, behavioral experiments were conducted. We assessed the effects of BAI on microglial activation, the production of proinflammatory cytokines, and neuroinflammation-mediated neuron apoptosis in vivo and in vitro using Western blot, RT-PCR, ELISA, immunohistochemistry, and immunofluorescence. Finally, to elucidate the anti-inflammation mechanisms underlying the effects of BAI, the protein expression of NLRP3 inflammasomes and the expression of proteins involved in the TLR4/NF-κB signaling pathway were measured using Western blot and immunofluorescence. RESULTS:The results indicated that BAI treatment attenuated spatial memory dysfunction in APP/PS1 mice, as assessed by the passive avoidance test and the Morris water maze test. Additionally, BAI administration effectively decreased the number of activated microglia and proinflammatory cytokines, as well as neuroinflammation-mediated neuron apoptosis, in APP/PS1 mice and LPS (lipopolysaccharides)/Aβ-stimulated BV2 microglial cells. Lastly, the molecular mechanistic study revealed that BAI inhibited microglia-induced neuroinflammation via suppression of the activation of NLRP3 inflammasomes and the TLR4/NF-κB signaling pathway. CONCLUSION:Overall, the results of the present study indicated that BAI is a promising neuroprotective compound for use in the prevention and treatment of microglia-mediated neuroinflammation during AD progression. 10.1111/cns.13086
    Baicalin Ameliorates Cognitive Impairment and Protects Microglia from LPS-Induced Neuroinflammation via the SIRT1/HMGB1 Pathway. Li Yue,Liu Taotao,Li Yitong,Han Dengyang,Hong Jingshu,Yang Ning,He Jindan,Peng Ronghui,Mi Xinning,Kuang Chongshen,Zhou Yang,Han Yongzheng,Shi Chengmei,Li Zhengqian,Guo Xiangyang Oxidative medicine and cellular longevity Systemic inflammation often induces neuroinflammation and disrupts neural functions, ultimately causing cognitive impairment. Furthermore, neuronal inflammation is the key cause of many neurological conditions. It is particularly important to develop effective neuroprotectants to prevent and control inflammatory brain diseases. Baicalin (BAI) has a wide variety of potent neuroprotective and cognitive enhancement properties in various models of neuronal injury through antioxidation, anti-inflammation, anti-apoptosis, and stimulating neurogenesis. Nevertheless, it remains unclear whether BAI can resolve neuroinflammation and cognitive decline triggered by systemic or distant inflammatory processes. In the present study, intraperitoneal lipopolysaccharide (LPS) administration was used to establish neuroinflammation to evaluate the potential neuroprotective and anti-inflammatory effects of BAI. Here, we report that BAI activated silent information regulator 1 (SIRT1) to deacetylate high-mobility group box 1 (HMGB1) protein in response to acute LPS-induced neuroinflammation and cognitive deficits. Furthermore, we demonstrated the anti-inflammatory and cognitive enhancement effects and the underlying molecular mechanisms of BAI in modulating microglial activation and systemic cytokine production, including tumor necrosis factor- (TNF-) and interleukin- (IL-) 1, after LPS exposure in mice and in the microglial cell line, BV2. In the hippocampus, BAI not only reduced reactive microglia and inflammatory cytokine production but also modulated SIRT1/HMGB1 signaling in microglia. Interestingly, pretreatment with SIRT1 inhibitor EX-527 abolished the beneficial effects of BAI against LPS exposure. Specifically, BAI treatment inhibited HMGB1 release via the SIRT1/HMGB1 pathway and reduced the nuclear translocation of HMGB1 in LPS-induced BV2 cells. These effects were reversed in BV2 cells by silencing endogenous . Taken together, these findings indicated that BAI reduced microglia-associated neuroinflammation and improved acute neurocognitive deficits in LPS-induced mice via SIRT1-dependent downregulation of HMGB1, suggesting a possible novel protection against acute neurobehavioral deficits, such as delayed neurocognitive recovery after anesthesia and surgery challenges. 10.1155/2020/4751349
    A pro-inflammatory mediator USP11 enhances the stability of p53 and inhibits KLF2 in intracerebral hemorrhage. Zhang Xiuqing,Liu Tiejun,Xu Shijun,Gao Peng,Dong Wei,Liu Weiran,Gao Ming,Song Lihua,Cui Lusha,Dong Xiaoliu Molecular therapy. Methods & clinical development Microglial cell activation and neuroinflammation after intracerebral hemorrhage (ICH) lead to secondary brain damage. Ubiquitin-specific protease 11 (USP11) has been correlated with ICH-induced neuron apoptosis. This study aims to explore the molecular mechanism of USP11 regulating neuroinflammation in ICH. First, an ICH rat model was developed by intracranial administration of collagenase. Silencing USP11 was found to alleviate nerve injury in rats with ICH-like symptoms. Then, through loss- and gain-of-function assays, USP11 knockdown was revealed to alleviate ICH-induced symptoms, corresponding to reduced modified neurological severity scores (mNSS) value, brain water content, blood-brain barrier permeability, neuron apoptosis, microglial cell activation, neutrophil infiltration, and inflammatory factor secretion. It was subsequently shown in microglial cells that USP11 stabilized p53 by deubiquitination and p53 targeted the Kruppel-like factor 2 (KLF2) promoter to repress KLF2 transcription, thereby activating the nuclear factor κB (NF-κB) pathway. Further, rescue experiments were conducted to validate the function of the USP11/p53/KLF2/NF-κB axis in ICH-induced inflammation, which confirmed that USP11 silencing blocked the release of pro-inflammatory cytokines following ICH by downregulating p53, thus protecting against neurological impairment. Hence silencing USP11 may be a novel anti-inflammatory method for ICH treatment. 10.1016/j.omtm.2021.01.015
    BAY61‑3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury. He Xuejun,Huang Yimin,Liu Yanchao,Zhang Xincheng,Yue Pengjie,Ma Xiaopeng,Miao Zhuangzhuang,Long Xiaobing,Yang Yiping,Wan Xueyan,Lei Jin,Shu Kai,Lei Ting,Gan Chao,Zhang Huaqiu International journal of molecular medicine Neuroinflammatory processes mediated by microglial activation and subsequent neuronal damage are the hallmarks of traumatic brain injury (TBI). As an inhibitor of the macrophage‑inducible C‑type lectin (Mincle)/spleen tyrosine kinase (Syk) signaling pathway, BAY61‑3606 (BAY) has previously demonstrated anti‑inflammatory effects on some pathological processes, such as acute kidney injury, by suppressing the inflammatory macrophage response. In the present study, the potential effects of BAY on microglial phenotype and neuroinflammation after TBI were investigated. BAY (3 mg/kg) was first administered into mice by intraperitoneal injection after TBI induction and microglia were also treated with BAY (2 µM) . The levels of inflammatory factors in microglia were assessed using reverse transcription‑quantitative PCR and ELISA. Cortical neuron, myelin sheath, astrocyte and cerebrovascular endothelial cell markers were detected using immunofluorescence. The levels of components of the Mincle/Syk/NF‑κB signaling pathway [Mincle, phosphorylated (p)‑Syk and NF‑κB], in addition to proteins associated with inflammation (ASC, caspase‑1, TNF‑α, IL‑1β and IL‑6), apoptosis (Bax and Bim) and tight junctions (Claudin‑5), were measured via western blotting and ELISA. Migration and chemotaxis of microglial cells were evaluated using Transwell and agarose spot assays. Neurological functions of the mice were determined using the modified neurological severity scoring system and a Morris water maze. The results of the present study revealed that the expression levels of proteins in the Mincle/Syk/NF‑κB signaling pathway (including Mincle, p‑Syk and p‑NF‑κB), inflammatory cytokines (TNF‑α, IL‑1β and IL‑6), proteins involved in inflammation (ASC and caspase‑1), apoptotic markers (Bax and Bim) and the tight junction protein Claudin‑5 were significantly altered post‑TBI. BAY treatment reversed these effects in both the cerebral cortex extract‑induced cell model and the controlled cortical impact mouse model. BAY was also revealed to suppress activation of the microglial proinflammatory phenotype and microglial migration. In addition, BAY effectively attenuated TBI‑induced neurovascular unit damage and neurological function deficits. Taken together, these findings provided evidence that BAY may inhibit the Mincle/Syk/NF‑κB signaling pathway in microglia; this in turn could attenuate microglia‑mediated neuroinflammation and improve neurological deficits following TBI. 10.3892/ijmm.2021.5060
    Cerebral Hemorrhage: Pathophysiology, Treatment, and Future Directions. Circulation research Intracerebral hemorrhage (ICH) is a devastating form of stroke with high morbidity and mortality. This review article focuses on the epidemiology, cause, mechanisms of injury, current treatment strategies, and future research directions of ICH. Incidence of hemorrhagic stroke has increased worldwide over the past 40 years, with shifts in the cause over time as hypertension management has improved and anticoagulant use has increased. Preclinical and clinical trials have elucidated the underlying ICH cause and mechanisms of injury from ICH including the complex interaction between edema, inflammation, iron-induced injury, and oxidative stress. Several trials have investigated optimal medical and surgical management of ICH without clear improvement in survival and functional outcomes. Ongoing research into novel approaches for ICH management provide hope for reducing the devastating effect of this disease in the future. Areas of promise in ICH therapy include prognostic biomarkers and primary prevention based on disease pathobiology, ultra-early hemostatic therapy, minimally invasive surgery, and perihematomal protection against inflammatory brain injury. 10.1161/CIRCRESAHA.121.319949
    Neuroinflammation Mediated by NLRP3 Inflammasome After Intracerebral Hemorrhage and Potential Therapeutic Targets. Xiao Linglong,Zheng Huaping,Li Jing,Wang Qinghua,Sun Haitao Molecular neurobiology Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke; there is still a lack of effective treatment. Microglia are a major component of the innate immune system, and they respond to acute brain injury by activating and forming classic M1-like (pro-inflammatory) or alternative M2-like (anti-inflammatory) phenotype. The existence of the polarization indicates that the role of microglia in disease's progression and recovery after ICH is still unclear, perhaps involving microglial secretion of anti-inflammatory or pro-inflammatory cytokines and chemokines. The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is considered to be the main participant in neuroinflammation. Recent evidence has shown that NLRP3 inflammasome can be activated after ICH, resulting in inflammatory cascade reactions and aggravating brain injury. Furthermore, previous studies have reported that NLRP3 inflammasome is mainly present in microglia, so we speculate that its activation may be strongly associated with microglial polarization. Many scholars have investigated the role of brain injury caused by NLRP3 inflammasome after ICH, but the precise operating mechanisms remain uncertain. This review summarized the activation mechanism of NLRP3 inflammasome after ICH and the possible mechanism of NLRP3 inflammasome promoting neuroinflammation and aggravating nerve injury and discussed the relevant potential therapeutic targets. 10.1007/s12035-020-02082-2
    Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets. Tschoe Christine,Bushnell Cheryl D,Duncan Pamela W,Alexander-Miller Martha A,Wolfe Stacey Q Journal of stroke Spontaneous intracerebral hemorrhage (ICH) is a catastrophic illness causing significant morbidity and mortality. Despite advances in surgical technique addressing primary brain injury caused by ICH, little progress has been made treating the subsequent inflammatory cascade. Pre-clinical studies have made advancements identifying components of neuroinflammation, including microglia, astrocytes, and T lymphocytes. After cerebral insult, inflammation is initially driven by the M1 microglia, secreting cytokines (e.g., interleukin-1β [IL-1β] and tumor necrosis factor-α) that are involved in the breakdown of the extracellular matrix, cellular integrity, and the blood brain barrier. Additionally, inflammatory factors recruit and induce differentiation of A1 reactive astrocytes and T helper 1 (Th1) cells, which contribute to the secretion of inflammatory cytokines, augmenting M1 polarization and potentiating inflammation. Within 7 days of ICH ictus, the M1 phenotype coverts to a M2 phenotype, key for hematoma removal, tissue healing, and overall resolution of inflammation. The secretion of anti-inflammatory cytokines (e.g., IL-4, IL-10) can drive Th2 cell differentiation. M2 polarization is maintained by the secretion of additional anti-inflammatory cytokines by the Th2 cells, suppressing M1 and Th1 phenotypes. Elucidating the timing and trigger of the anti-inflammatory phenotype may be integral in improving clinical outcomes. A challenge in current translational research is the absence of an equivalent disease animal model mirroring the patient population and comorbid pathophysiologic state. We review existing data and describe potential therapeutic targets around which we are creating a bench to bedside translational research model that better reflects the pathophysiology of ICH patients. 10.5853/jos.2019.02236
    BM-MSC Transplantation Alleviates Intracerebral Hemorrhage-Induced Brain Injury, Promotes Astrocytes Vimentin Expression, and Enhances Astrocytes Antioxidation via the Cx43/Nrf2/HO-1 Axis. Chen Xiao,Liang Huaibin,Xi Zhiyu,Yang Yong,Shan Huimin,Wang Baofeng,Zhong Zhihong,Xu Canxin,Yang Guo-Yuan,Sun Qingfang,Sun Yuhao,Bian Liuguan Frontiers in cell and developmental biology Intracerebral hemorrhage (ICH) is a particularly severe form of stroke, and reactive astrogliosis is a common response following injury to the central nervous system (CNS). Mesenchymal stem cells (MSCs) are reported to promote neurogenesis and alleviate the late side effects in injured brain regions. Gap junctions (Gjs) are abundant in the brain, where the richest connexin (Cx) is Cx43, most prominently expressed in astrocytes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor regulating antioxidant reactions. Here, we aimed to explore whether bone marrow MSCs (BM-MSCs) could alleviate brain injury and protect astrocytes from apoptosis, by regulating Cx43 and Nrf2. We validated the effect of BM-MSC transplantation in an ICH model and and detected changes using immunofluorescence, as well as protein and mRNA expression of glial fibrillary acidic protein (GFAP), vimentin (VIM), Cx43, Nrf2, and heme oxygenase-1 (HO-1). Our results showed that BM-MSC transplantation attenuated brain injury after ICH and upregulated VIM expression and . Additionally, Cx43 upregulation and Nrf2 nuclear translocation were observed in astrocytes cocultured with BM-MSC. Knockdown of Cx43 by siRNA restrained Nrf2 nuclear translocation. Cx43 and Nrf2 had a connection as determined by immunofluorescence and coimmunoprecipitation. We demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and have anti-apoptotic abilities after BM-MSC transplantation, where Cx43 upregulation triggers Nrf2 nuclear translocation and promotes its phase II enzyme expression. The Cx43/Nrf2 interaction of astrocytes after BM-MSC transplantation may provide an important therapeutic target in the management of ICH. 10.3389/fcell.2020.00302
    Bone marrow mesenchymal stem cells transplantation alleviates brain injury after intracerebral hemorrhage in mice through the Hippo signaling pathway. Chen Xiao,Xu Can-Xin,Liang Huaibin,Xi Zhiyu,Pan Jiaji,Yang Yong,Sun Qingfang,Yang Guoyuan,Sun Yuhao,Bian Liuguan Aging Intracerebral hemorrhage (ICH) is a common acute nervous system disease with high mortality and severe disability. Mesenchymal stem cells (MSCs) have been reported to promote neurogenesis and to alleviate side effects in areas of brain injury areas. The Hippo pathway regulates diverse cellular processes, including cell survival, proliferation, differentiation, and organ size. Here, we found that transplantation of bone marrow MSCs (BM-MSCs) into the brains of mice could alleviate ICH-mediated injury and protect astrocytes from apoptosis by regulating mammalian sterile 20-like kinase (MST)1 and Yes-associated protein (YAP). Knocking down of MST1 by si-RNA triggered YAP nuclear translocation. We further demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and become capable of proliferating after BM-MSC transplantation via the Hippo signaling pathway. Together, our identification of the Hippo pathway in mediating the beneficial effects of BM-MSCs may provide a novel therapeutic target in the treatment and management of ICH. 10.18632/aging.103025
    Astrocytes: a central element in neurological diseases. Pekny Milos,Pekna Marcela,Messing Albee,Steinhäuser Christian,Lee Jin-Moo,Parpura Vladimir,Hol Elly M,Sofroniew Michael V,Verkhratsky Alexei Acta neuropathologica The neurone-centred view of the past disregarded or downplayed the role of astroglia as a primary component in the pathogenesis of neurological diseases. As this concept is changing, so is also the perceived role of astrocytes in the healthy and diseased brain and spinal cord. We have started to unravel the different signalling mechanisms that trigger specific molecular, morphological and functional changes in reactive astrocytes that are critical for repairing tissue and maintaining function in CNS pathologies, such as neurotrauma, stroke, or neurodegenerative diseases. An increasing body of evidence shows that the effects of astrogliosis on the neural tissue and its functions are not uniform or stereotypic, but vary in a context-specific manner from astrogliosis being an adaptive beneficial response under some circumstances to a maladaptive and deleterious process in another context. There is a growing support for the concept of astrocytopathies in which the disruption of normal astrocyte functions, astrodegeneration or dysfunctional/maladaptive astrogliosis are the primary cause or the main factor in neurological dysfunction and disease. This review describes the multiple roles of astrocytes in the healthy CNS, discusses the diversity of astroglial responses in neurological disorders and argues that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer's disease as well as other neurodegenerative diseases. 10.1007/s00401-015-1513-1
    A Novel Brainstem Hemorrhage Model by Autologous Blood Infusion in Rat: White Matter Injury, Magnetic Resonance Imaging, and Neurobehavioral Features. Tao Chuanyuan,Zhang Ruzhi,Hu Xin,Song Li,Wang Chunhua,Gao Fabao,You Chao Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association BACKGROUND:Primary brainstem hemorrhage (BSH) has the highest mortality and morbidity as a subtype of intracerebral hemorrhage. A major limitation of BSH research is the lack of a corresponding animal model. The purpose of this study was to establish a novel rat model of BSH and to characterize the resulting brain injury, especially focusing on white matter injury. METHODS:BSH was produced by stereotactically injecting autologous whole blood into the pons. Time course of hematoma resolution was observed by 7-T magnetic resonance imaging. White matter injury was evaluated in detail by multiple parameters including diffuse tensor imaging (DTI), demyelination, axonal injury, oligodendrocyte degeneration, and oligodendrocyte precursor cell proliferation. Brain water content and neurobehavior were also evaluated. RESULTS:Blood infusion (30 µL) led to a stable, reproducible hematoma in the right basotegmental pons. The hematoma absorption started, became obvious, and was nearly completed at 7, 14, and 30 days, respectively. Hematoma caused obvious brain edema at 3 days. White mater injury was observed pathologically, which was in line with decreased fractional anisotropy (FA) in DTI in the pons. FA reduction was also noticed in the cerebral peduncle and medulla. Behavioral abnormality persisted for at least 14 days and neurofunction was recovered within 1 month. CONCLUSIONS:This novel model can produce a stable hematoma resulting in brain edema, white matter injury, and neurofunctional deficits, which could be useful for future investigation of pathophysiological mechanisms and new treatment evaluation after BSH. 10.1016/j.jstrokecerebrovasdis.2016.01.025
    White matter injury in young and aged rats after intracerebral hemorrhage. Wasserman Jason K,Schlichter Lyanne C Experimental neurology Experimental studies of intracerebral hemorrhage (ICH) have focused on neuron death, with little or no information on axonal and myelin damage outside the hematoma. Because development of effective therapies will require an understanding of white matter injury, we examined white matter injury and its spatial and temporal relationship with microglial/macrophage activation in a collagenase model of rat striatal ICH. The hematoma and parenchyma surrounding the hematoma were assessed in young and aged animals at 6 h, 1, 3 and 28 days after ICH onset. Demyelination occurred inside and at the edge of the hematoma; regions where we have shown substantial neuron death. In contrast, there was axonal damage without demyelination at the edge of the hematoma, and by 3 days this damage had spread to the surrounding parenchyma, a region where we have shown there is no neuron death. Because the axonal damage preceded infiltration of activated microglia into the white matter tracts (seen at 3 days), our results support the hypothesis that these cells respond to, rather than perpetrate the damage. Importantly, axonal damage was worse in aged animals, which provides a plausible explanation for the poorer functional recovery of older animals after ICH, despite a similar loss of grey matter. Our findings support strategies that target white matter injury to reduce neurological impairment after ICH. 10.1016/j.expneurol.2008.08.010
    Therapeutic Benefits of Mesenchymal Stromal Cells in a Rat Model of Hemoglobin-Induced Hypertensive Intracerebral Hemorrhage. Ding Rui,Lin Chunnan,Wei ShanShan,Zhang Naichong,Tang Liangang,Lin Yumao,Chen Zhijun,Xie Teng,Chen XiaoWei,Feng Yu,Wu LiHua Molecules and cells Previous studies have shown that bone marrow mesenchymal stromal cell (MSC) transplantation significantly improves the recovery of neurological function in a rat model of intracerebral hemorrhage. Potential repair mechanisms involve anti-inflammation, anti-apoptosis and angiogenesis. However, few studies have focused on the effects of MSCs on inducible nitric oxide synthase (iNOS) expression and subsequent peroxynitrite formation after hypertensive intracerebral hemorrhage (HICH). In this study, MSCs were transplanted intracerebrally into rats 6 hours after HICH. The modified neurological severity score and the modified limb placing test were used to measure behavioral outcomes. Blood-brain barrier disruption and neuronal loss were measured by zonula occludens-1 (ZO-1) and neuronal nucleus (NeuN) expression, respectively. Concomitant edema formation was evaluated by H&E staining and brain water content. The effect of MSCs treatment on neuroinflammation was analyzed by immunohistochemical analysis or polymerase chain reaction of CD68, Iba1, iNOS expression and subsequent peroxynitrite formation, and by an enzyme-linked immunosorbent assay of pro-inflammatory factors (IL-1β and TNF-α). The MSCs-treated HICH group showed better performance on behavioral scores and lower brain water content compared to controls. Moreover, the MSC injection increased NeuN and ZO-1 expression measured by immunochemistry/immunofluorescence. Furthermore, MSCs reduced not only levels of CD68, Iba1 and pro-inflammatory factors, but it also inhibited iNOS expression and peroxynitrite formation in perihematomal regions. The results suggest that intracerebral administration of MSCs accelerates neurological function recovery in HICH rats. This may result from the ability of MSCs to suppress inflammation, at least in part, by inhibiting iNOS expression and subsequent peroxynitrite formation. 10.14348/molcells.2017.2251
    The Effect of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in a Collagenase-Induced Intracerebral Hemorrhage Rat Model. Kim Kwanwoo,Park Hyung Woo,Moon Hyo-Eun,Kim Jin Wook,Bae Seongtae,Chang Jong Wook,Oh Wonil,Yang Yoon Sun,Paek Sun Ha Experimental neurobiology Intracerebral hemorrhage (ICH) is one of the devastating types of stroke. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have potential benefits in recovery from brain damage following ICH. This study aimed to identify the beneficial effects of hUCB-MSCs and investigate whether they have anti-inflammatory effects on the ICH brain via neurotrophic factors or cytokines. hUCB-MSCs were transplanted into a collagenase-induced ICH rat model. At 2, 9, 16, and 30 days after ICH, rotarod and limb placement tests were performed to measure behavioral outcomes. ICH rats were sacrificed to evaluate the volume of lesion using H&E staining. Immunostaining was performed to investigate neurogenesis, angiogenesis, and anti-apoptosis at 4 weeks after transplantation. Inflammatory factors (TNF-α, COX-2, microglia, and neutrophils) were analyzed by immunofluorescence staining, RT-PCR, and Western blot at 3 days after transplantation. hUCB-MSCs were associated with neurological benefits and reduction in lesion volume. The hUCB-MSCs-treated group tended to reveal high levels of neurogenesis, angiogenesis, and anti-apoptosis (significant for angiogenesis). The expression levels of inflammatory factors tended to be reduced in the hUCB-MSCs-treated group compared with the controls. Our study suggests that hUCB-MSCs may improve neurological outcomes and modulate inflammation-associated immune cells and cytokines in ICH-induced inflammatory responses. 10.5607/en.2015.24.2.146
    Natural history of perihematomal edema in patients with hyperacute spontaneous intracerebral hemorrhage. Gebel James M,Jauch Edward C,Brott Thomas G,Khoury Jane,Sauerbeck Laura,Salisbury Shelia,Spilker Judith,Tomsick Thomas A,Duldner John,Broderick Joseph P Stroke BACKGROUND AND PURPOSE:The natural history of perihematomal edema in human hyperacute spontaneous intracerebral hemorrhage (ICH) has not been well described. METHODS:This study was a secondary analysis of a previously reported prospective, population-based study of hematoma growth in 142 patients with spontaneous ICH. Patients were first imaged within 3 hours of onset, then 1 and 20 hours later. We excluded patients with anticoagulant use (n=7), underlying aneurysm/vascular malformation (n=9), trauma (n=1), incomplete data (n=20), infratentorial ICH (n=17), and no consent (n=2), leaving an overall study population of 86 patients. From this overall group we further excluded patients with intraventricular extension (n=38), subsequent surgery (n=5), or death (n=2) before 20-hour postbaseline CT. This second, "restricted" analysis group of 41 patients was relatively devoid of clinical or radiological variables likely to confound edema measurement. Absolute and relative edema volumes (edema volume divided by hematoma volume) were descriptively summarized. Correlations between baseline edema volumes and relevant clinical and radiological variables were then performed. RESULTS:Overall, median absolute edema volume increased from 6.93 to 14.4 cm(3) during the first 24 hours after ICH, and median relative edema volume increased from 0.47 to 0.81. In the restricted group, median absolute edema volume was 7.4 cm(3) at baseline and 11.0 cm(3) at 24 hours after ICH, and median relative edema volume increased from 0.55 to 0.81. Baseline relative edema volume was significantly negatively correlated with subsequent change in relative edema volume from baseline to 20-hour CT (r=0.57, P=0.0002) but was not significantly correlated with other clinical and radiological variables, including hematoma volume or change in hematoma volume. CONCLUSIONS:Perihematomal edema volume increases by approximately 75% during the first 24 hours after hyperacute spontaneous ICH. Patients with the least amounts of baseline relative edema volume were most likely to develop significant additional amounts of edema during the first 24 hours after spontaneous ICH.
    Minocycline Preserves the Integrity and Permeability of BBB by Altering the Activity of DKK1-Wnt Signaling in ICH Model. Wang Guoqing,Li Zhihua,Li Shujian,Ren Junling,Suresh Vigneyshwar,Xu Dingkang,Zang Weidong,Liu Xianzhi,Li Wei,Wang Huizhi,Guo Fuyou Neuroscience Disruption of the blood-brain barrier (BBB) and subsequent neurological deficits are the most severe consequence of intracerebral hemorrhage (ICH). Minocycline has been wildly used clinically as a neurological protective agent in clinical practice. However, the underlying mechanisms by which minocycline functions remain unclear. Therefore, we assessed the influence of minocycline on BBB structure, neurological function, and inflammatory responses in a collagenase-induced ICH model, and elucidated underlying molecular mechanisms as well. Following a single injection of collagenase VII-S into the basal ganglia, BBB integrity was assessed by Evans blue extravasation while neurological function was assessed using an established neurologic function scoring system. Minocycline treatment significantly alleviated the severity of BBB disruption, brain edema, and neurological deficits in ICH model. Moreover, minocycline decreased the production of inflammatory mediators including TNF, IL-6, and MMP-9, by microglia. Minocycline treatment decreased DKK1 expression but increased Wnt1, β-catenin and Occludin, a phenomenon mimicked by DKK1 silencing. These data suggest that minocycline improves the consequences of ICH by preserving BBB integrity and attenuating neurologic deficits in a DKK1-related manner that involves enhancement of the Wnt1-β-catenin activity. 10.1016/j.neuroscience.2019.06.038
    Targeting secondary injury in intracerebral haemorrhage--perihaematomal oedema. Urday Sebastian,Kimberly W Taylor,Beslow Lauren A,Vortmeyer Alexander O,Selim Magdy H,Rosand Jonathan,Simard J Marc,Sheth Kevin N Nature reviews. Neurology Perihaematomal oedema (PHO) is an important pathophysiological marker of secondary injury in intracerebral haemorrhage (ICH). In this Review, we describe a novel method to conceptualize PHO formation within the framework of Starling's principle of movement of fluid across a capillary wall. We consider progression of PHO through three stages, characterized by ionic oedema (stage 1) and progressive vasogenic oedema (stages 2 and 3). In this context, possible modifiers of PHO volume and their value in identifying patients who would benefit from therapies that target secondary injury are discussed; the practicalities of using neuroimaging to measure PHO volume are also considered. We examine whether PHO can be used as a predictor of neurological outcome following ICH, and we provide an overview of emerging therapies. Our discussion emphasizes that PHO has clinical relevance both as a therapeutic target, owing to its augmentation of the mass effect of a haemorrhage, and as a surrogate marker for novel interventions that target secondary injury. 10.1038/nrneurol.2014.264
    Brain transforms natural killer cells that exacerbate brain edema after intracerebral hemorrhage. Li Zhiguo,Li Minshu,Shi Samuel X,Yao Nan,Cheng Xiaojing,Guo Ai,Zhu Zilong,Zhang Xiaoan,Liu Qiang The Journal of experimental medicine Perihematomal edema (PHE) occurs within hours after intracerebral hemorrhage (ICH), leading to secondary injury manifested by impaired blood-brain barrier (BBB) integrity and destruction of adjacent tissue. To dissect the mechanisms underlying PHE formation, we profiled human and mouse perihematomal tissues and identified natural killer (NK) cells as the predominant immune cell subset that outnumbers other infiltrating immune cell types during early stages of ICH. Unbiased clustering of single-cell transcriptional profiles revealed two major NK cell subsets that respectively possess high cytotoxicity or robust chemokine production features in the brain after ICH, distinguishing them from NK cells of the periphery. NK cells exacerbate BBB disruption and brain edema after ICH via cytotoxicity toward cerebral endothelial cells and recruitment of neutrophils that augment focal inflammation. Thus, brain-bound NK cells acquire new features that contribute to PHE formation and neurological deterioration following ICH. 10.1084/jem.20200213
    Perihematomal edema: Implications for intracerebral hemorrhage research and therapeutic advances. Selim Magdy,Norton Casey Journal of neuroscience research In humans, perihematomal edema (PHE) is considered to be a radiological marker of secondary injury following intracerebral hemorrhage (ICH). There is also evidence that PHE might contribute to poor outcome in ICH patients. Given the rising interest in secondary injury after ICH as a therapeutic target, PHE is becoming increasingly used as a proof-of-concept surrogate measure to assess the potential efficacy of various therapeutic interventions in clinical trials. We review the pathophysiology of PHE and its evolution, its prognostic significance and relationship to clinical outcomes, and variabilities in its detection and measurement methodologies to determine the advantages versus shortcomings of using PHE as a translational target or radiological marker to examine the efficacy of interventions aiming to mitigate secondary injury in ICH. 10.1002/jnr.24372
    Sevoflurane postconditioning attenuates reactive astrogliosis and glial scar formation after ischemia-reperfusion brain injury. Zhu Yong-Ming,Gao Xue,Ni Yong,Li Wei,Kent Thomas A,Qiao Shi-Gang,Wang Chen,Xu Xiao-Xuan,Zhang Hui-Ling Neuroscience Cerebral ischemia leads to astrocyte's activation and glial scar formation. Glial scar can inhibit axonal regeneration during the recovery phase. It has demonstrated that sevoflurane has neuroprotective effects against ischemic stroke, but its effects on ischemia-induced formation of astrogliosis and glial scar are unknown. This study was designed to investigate the effect of sevoflurane postconditioning on astrogliosis and glial scar formation in ischemic stroke model both in vivo and in vitro. The results showed that 2.5% of sevoflurane postconditioning could significantly reduce infarction volume and improve neurologic deficits. And it could also decrease the expression of the glial scar marker glial fibrillary acidic protein (GFAP), neurocan and phosphacan in the peri-infarct region and markedly reduce the thickness of glial scar after ischemia/reperfusion (I/R). Consistent with the in vivo data, in the oxygen and glucose deprivation/reoxygenation (OGD/Re) model, sevoflurane postconditioning could protect astrocyte against OGD/Re-induced injury, decrease the expression of GFAP, neurocan and phosphacan. Further studies demonstrated that sevoflurane postconditioning could down-regulate the expression of Lamp1 and active cathepsin B, and block I/R or OGD/Re-induced release of cathepsin B from the lysosomes into cytoplasm. In order to confirm whether inhibition of cathepsin B could attenuate the formation of glial scar, we used cathepsin B inhibitor CA-074Me as a positive control. The results showed that inhibition of cathepsin B could decrease the expression of GFAP, neurocan and phosphacan. Taken together, sevoflurane postconditioning can attenuate astrogliosis and glial scar formation after ischemic stroke, associating with inhibition of the activation and release of lysosomal cathepsin B. 10.1016/j.neuroscience.2017.05.004
    Astrocyte reactivity and reactive astrogliosis: costs and benefits. Pekny Milos,Pekna Marcela Physiological reviews Astrocytes are the most abundant cells in the central nervous system (CNS) that provide nutrients, recycle neurotransmitters, as well as fulfill a wide range of other homeostasis maintaining functions. During the past two decades, astrocytes emerged also as increasingly important regulators of neuronal functions including the generation of new nerve cells and structural as well as functional synapse remodeling. Reactive gliosis or reactive astrogliosis is a term coined for the morphological and functional changes seen in astroglial cells/astrocytes responding to CNS injury and other neurological diseases. Whereas this defensive reaction of astrocytes is conceivably aimed at handling the acute stress, limiting tissue damage, and restoring homeostasis, it may also inhibit adaptive neural plasticity mechanisms underlying recovery of function. Understanding the multifaceted roles of astrocytes in the healthy and diseased CNS will undoubtedly contribute to the development of treatment strategies that will, in a context-dependent manner and at appropriate time points, modulate reactive astrogliosis to promote brain repair and reduce the neurological impairment. 10.1152/physrev.00041.2013
    Association of , , and With Parkinson's Disease in Southern Chinese. Li Gen,Cui Shishuang,Du Juanjuan,Liu Jin,Zhang Pingchen,Fu Yang,He Yixi,Zhou Haiyan,Ma Jianfang,Chen Shengdi Frontiers in aging neuroscience The aim of the study was to investigate the relationship between 22 single nucleotide polymorphisms (SNPs) and Parkinson's disease (PD) in the Chinese population. A total of 250 PD patients and 240 healthy controls were recruited. The SNaPshot technique and the polymer chain reaction were used to detect 22 SNPs. rs8005172 of , rs9468199 of and rs34043159 of , were associated with PD (rs8005172: = 0.009, OR = 0.69, allele model, = 0.010, additive model, = 0.015, OR = 2.17, dominant model; = 0.020, OR = 2.11, dominant model after adjustment; = 0.036, OR = 1.47, recessive model after adjustment; rs9468199: = 0.008, OR = 1.52, allele model, = 0.008, additive model, = 0.007, OR = 0.22, recessive model, = 0.005, OR = 0.20, recessive model after adjustment; rs34043159: = 0.034, OR = 1.31, allele model, = 0.036, additive model). Our study revealed that , , and were associated with PD in the southern Chinese population. was also associated with LOPD. and were associated with EOPD. In addition, trends of association to PD, between , , and , were also found. Genetic play an important role in the pathogenesis factors of Parkinson's disease (PD). We found that , , and were associated with PD. was also associated with late onset of PD, while and were associated with early onset PD. This study is the first to find an association between , , and rs2280104 with PD. 10.3389/fnagi.2018.00402
    Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction. Weinstock Nadav I,Shin Daesung,Dhimal Narayan,Hong Xinying,Irons Eric E,Silvestri Nicholas J,Reed Chelsey B,Nguyen Duc,Sampson Oliver,Cheng Yung-Chih,Lau Joseph T Y,Bongarzone Ernesto R,Kofler Julia,Escolar Maria L,Gelb Michael H,Wrabetz Lawrence,Feltri M Laura Neuron Many therapies for lysosomal storage disorders rely on cross-correction of lysosomal enzymes. In globoid cell leukodystrophy (GLD), mutations in GALC cause psychosine accumulation, inducing demyelination, a neuroinflammatory "globoid" reaction and neurodegeneration. The efficiency of GALC cross-correction in vivo, the role of the GALC substrate galactosylceramide, and the origin of psychosine are poorly understood. Using a novel GLD model, we show that cross-correction does not occur efficiently in vivo and that Galc-deficient Schwann cells autonomously produce psychosine. Furthermore, macrophages require GALC to degrade myelin, as Galc-deficient macrophages are transformed into globoid cells by exposure to galactosylceramide and produce a more severe GLD phenotype. Finally, hematopoietic stem cell transplantation in patients reduces globoid cells in nerves, suggesting that the phagocytic response of healthy macrophages, rather than cross-correction, contributes to the therapeutic effect. Thus, GLD may be caused by at least two mechanisms: psychosine-induced demyelination and secondary neuroinflammation from galactosylceramide storage in macrophages. 10.1016/j.neuron.2020.03.031
    MSCs-Derived Exosomes and Neuroinflammation, Neurogenesis and Therapy of Traumatic Brain Injury. Yang Yongxiang,Ye Yuqin,Su Xinhong,He Jun,Bai Wei,He Xiaosheng Frontiers in cellular neuroscience Exosomes are endosomal origin membrane-enclosed small vesicles (30-100 nm) that contain various molecular constituents including proteins, lipids, mRNAs and microRNAs. Accumulating studies demonstrated that exosomes initiated and regulated neuroinflammation, modified neurogenic niches and neurogenesis, and were even of potential significance in treating some neurological diseases. These tiny extracellular vesicles (EVs) can derive from some kinds of multipotent cells such as mesenchymal stem cells (MSCs) that have been confirmed to be a potentially promising therapy for traumatic brain injury (TBI) in experimental models and in preclinical studies. Nevertheless, subsequent studies demonstrated that the predominant mechanisms of MSCs's contributions to brain tissue repairment and functional recovery after TBI were not the cell replacement effects but likely the secretion-based paracrine effects produced by EVs such as MSCs-derived exosomes. These nanosized exosomes derived from MSCs cannot proliferate, are easier to preserve and transfer and have lower immunogenicity, compared with transplanted exogenous MSCs. These reports revealed that MSCs-derived exosomes might promise to be a new and valuable therapeutic strategy for TBI than MSCs themselves. However, the concrete mechanisms involved in the positive effects induced by MSCs-derived exosomes in TBI are still ambiguous. In this review, we intend to explore the potential effects of MSCs-derived exosomes on neuroinflammation and neurogenesis in TBI and, especially, on therapy. 10.3389/fncel.2017.00055
    Functional role of mesenchymal stem cells in the treatment of chronic neurodegenerative diseases. Lo Furno Debora,Mannino Giuliana,Giuffrida Rosario Journal of cellular physiology Mesenchymal stem cells (MSCs) can differentiate into not only cells of mesodermal lineages, but also into endodermal and ectodermal derived elements, including neurons and glial cells. For this reason, MSCs have been extensively investigated to develop cell-based therapeutic strategies, especially in pathologies whose pharmacological treatments give poor results, if any. As in the case of irreversible neurological disorders characterized by progressive neuronal death, in which behavioral and cognitive functions of patients inexorably decline as the disease progresses. In this review, we focus on the possible functional role exerted by MSCs in the treatment of some disabling neurodegenerative disorders such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Parkinson's Disease. Investigations have been mainly performed in vitro and in animal models by using MSCs generally originated from umbilical cord, bone marrow, or adipose tissue. Positive results obtained have prompted several clinical trials, the number of which is progressively increasing worldwide. To date, many of them have been primarily addressed to verify the safety of the procedures but some improvements have already been reported, fortunately. Although the exact mechanisms of MSC-induced beneficial activities are not entirely defined, they include neurogenesis and angiogenesis stimulation, antiapoptotic, immunomodulatory, and anti-inflammatory actions. Most effects would be exerted through their paracrine expression of neurotrophic factors and cytokines, mainly delivered at damaged regions, given the innate propensity of MSCs to home to injured sites. Hopefully, in the near future more efficacious cell-replacement therapies will be developed to substantially restore disease-disrupted brain circuitry. 10.1002/jcp.26192
    Bone marrow mesenchymal stem cell therapy in ischemic stroke: mechanisms of action and treatment optimization strategies. Li Guihong,Yu Fengbo,Lei Ting,Gao Haijun,Li Peiwen,Sun Yuxue,Huang Haiyan,Mu Qingchun Neural regeneration research Animal and clinical studies have confirmed the therapeutic effect of bone marrow mesenchymal stem cells on cerebral ischemia, but their mechanisms of action remain poorly understood. Here, we summarize the transplantation approaches, directional migration, differentiation, replacement, neural circuit reconstruction, angiogenesis, neurotrophic factor secretion, apoptosis, immunomodulation, multiple mechanisms of action, and optimization strategies for bone marrow mesenchymal stem cells in the treatment of ischemic stroke. We also explore the safety of bone marrow mesenchymal stem cell transplantation and conclude that bone marrow mesenchymal stem cell transplantation is an important direction for future treatment of cerebral ischemia. Determining the optimal timing and dose for the transplantation are important directions for future research. 10.4103/1673-5374.184506
    Functional outcome and survival following spontaneous intracerebral hemorrhage: A retrospective population-based study. Øie Lise R,Madsbu Mattis A,Solheim Ole,Jakola Asgeir S,Giannadakis Charalampis,Vorhaug Anders,Padayachy Llewellyn,Jensberg Heidi,Dodick David,Salvesen Øyvind,Gulati Sasha Brain and behavior BACKGROUND:Accurate and reliable clinical and radiological predictors of intracerebral hemorrhage (ICH) outcomes are needed to optimize treatment of ICH. The aim of this study was to investigate functional outcome and identify predictors of severe disability or death following ICH. MATERIALS AND METHODS:Retrospective population-based study of spontaneous ICH. Clinical and radiological data were obtained from electronic medical records, and functional outcome estimated using the modified Rankin Scale (mRS) before ICH and at 3 and 12 months after ICH. RESULTS:Four hundred and fifty-two patients were included (mean age 74.8 years, 45.6% females). Proportion of fatal outcome at 1 week was 22.1%, at 3 months 39.2%, and at 12 months 44.9%. Median mRS score before the ICH was 1 (interquartile range [IQR] 2); for survivors at 3 months, it was 5 (IQR 3); and at 12 months, it was 3 (IQR 2). Independent predictors of severe disability (mRS of 5) or death (mRS of 6) were use of oral antithrombotic drugs (OR 2.2, 95% CI 1.3-3.8, p = 0.04), mRS score before the ICH (OR 1.8, 95% CI 1.4-2.2, p < 0.001), Glasgow Coma Scale (GCS) on admission (OR 8.3, 95% CI 3.5-19.7, p < 0.001), hematoma volume >60 ml (OR 4.5, 05% CI 2.0-10.2, p < 0.001), and intraventricular hematoma extension (OR 1.8, 95% CI 0.8-4.2, p < 0.001). CONCLUSION:Intracerebral hemorrhage is associated with high mortality, and more than one third of survivors end up with severe disability or death 3 months later. Predictors of severe disability or death were use of oral antithrombotic drugs, functional disability prior to ICH, low GCS on admission, larger hematoma volume, and intraventricular hematoma extension. 10.1002/brb3.1113
    Cognitive impairment and dementia after intracerebral hemorrhage: a cross-sectional study of a hospital-based series. Garcia Pierre Yves,Roussel Martine,Bugnicourt Jean Marc,Lamy Chantal,Canaple Sandrine,Peltier Johan,Loas Gwénolé,Deramond Hervé,Godefroy Olivier Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association BACKGROUND:Frequencies of cognitive impairment and dementia have not been assessed in spontaneous intracerebral hemorrhage (ICH). The objective of this study was to determine the frequencies and patterns of cognitive impairment and dementia in a cross-sectional study of consecutive patients hospitalized in a single university medical center. METHODS:Of 183 consecutive patients hospitalized between 2002 and 2006, 80 survivors were contacted and 78 were included (mean time since stroke 40 months). Thirty patients were scored with the Informant Questionnaire on Cognitive Decline in the Elderly and Instrumental Activities of Daily Living in a telephone interview, and 48 underwent a comprehensive clinical and neuropsychological assessment. RESULTS:Dementia was observed in 18 of 78 patients (23%; 95% confidence interval [CI] 13-32%) and cognitive impairment without dementia was seen in 37 of 48 patients (77%; 95% CI 65-89%). The cognitive disorders mainly concerned episodic memory (52%), psychomotor speed (44%), and executive function (37%), followed by language and visuoconstructive abilities. In a logistic regression analysis, Rankin score >1 at discharge and hemorrhage volume were the initial factors to be selected as a predictor of long-term dementia. CONCLUSIONS:This single-center, cross-sectional study revealed that the prevalence of dementia and cognitive impairment without dementia after ICH are high and are similar to those observed in cerebral infarct. Further longitudinal, prospective studies are required to assess accurately the prevalence, mechanisms and predictors of post-ICH dementia. 10.1016/j.jstrokecerebrovasdis.2011.06.013
    Intracerebral haemorrhage: current approaches to acute management. Cordonnier Charlotte,Demchuk Andrew,Ziai Wendy,Anderson Craig S Lancet (London, England) Acute spontaneous intracerebral haemorrhage is a life-threatening illness of global importance, with a poor prognosis and few proven treatments. As a heterogeneous disease, certain clinical and imaging features help identify the cause, prognosis, and how to manage the disease. Survival and recovery from intracerebral haemorrhage are related to the site, mass effect, and intracranial pressure from the underlying haematoma, and by subsequent cerebral oedema from perihaematomal neurotoxicity or inflammation and complications from prolonged neurological dysfunction. A moderate level of evidence supports there being beneficial effects of active management goals with avoidance of early palliative care orders, well-coordinated specialist stroke unit care, targeted neurointensive and surgical interventions, early control of elevated blood pressure, and rapid reversal of abnormal coagulation. 10.1016/S0140-6736(18)31878-6
    Pathophysiological Mechanisms and Potential Therapeutic Targets in Intracerebral Hemorrhage. Shao Zhiwei,Tu Sheng,Shao Anwen Frontiers in pharmacology Intracerebral hemorrhage (ICH) is a subtype of hemorrhagic stroke with high mortality and morbidity. The resulting hematoma within brain parenchyma induces a series of adverse events causing primary and secondary brain injury. The mechanism of injury after ICH is very complicated and has not yet been illuminated. This review discusses some key pathophysiology mechanisms in ICH such as oxidative stress (OS), inflammation, iron toxicity, and thrombin formation. The corresponding therapeutic targets and therapeutic strategies are also reviewed. 10.3389/fphar.2019.01079
    Quercetin promotes neuronal and behavioral recovery by suppressing inflammatory response and apoptosis in a rat model of intracerebral hemorrhage. Zhang Yifan,Yi Bo,Ma Jianhua,Zhang Li,Zhang Hongtian,Yang Yi,Dai Yiwu Neurochemical research Intracerebral hemorrhage (ICH) is a common and devastating disease affecting millions of people worldwide annually. Exaggerated inflammation and apoptosis are two pivotal pathological processes for secondary brain injury after ICH. Quercetin, a flavonoid widely distributed in various herbs, fruits and vegetables, has been proved to improve neuronal functional recovery in spinal cord injury rats. However, the efficacy of quercetin in caring for post-ICH brain injury has not been investigated. In the present study, we established an ICH model by injecting type VII bacterial collagenase (0.5U) into the central striatum of male Sprague-Dawley rats. The animals were randomized to four groups: sham-operation group; ICH + vehicle group; ICH + 5 mg/kg quercetin group; and ICH + 50 mg/kg quercetin group. The expression levels of IL-1β, IL-4, IL-6 and TNF-α in the brain tissue were assayed by Real-time PCR, ELISA and Western Blot, and cell apoptosis was assayed by TUNEL and caspase-3 staining 3 days after model establishment. It was found that the lesion volume, the brain water content, the expression levels of the four inflammation markers and the number of apoptotic cells were reduced significantly in ICH rats receiving quercetin, especially in 50 mg/kg quercetin group. These results confirmed the therapeutic efficacy of quercetin in repairing brain injury, probably by inhibiting inflammatory response and apoptosis, thus promoting nerve functional restoration. 10.1007/s11064-014-1457-1
    Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Feigin Valery L,Lawes Carlene M M,Bennett Derrick A,Barker-Collo Suzanne L,Parag Varsha The Lancet. Neurology This systematic review of population-based studies of the incidence and early (21 days to 1 month) case fatality of stroke is based on studies published from 1970 to 2008. Stroke incidence (incident strokes only) and case fatality from 21 days to 1 month post-stroke were analysed by four decades of study, two country income groups (high-income countries and low to middle income countries, in accordance with the World Bank's country classification) and, when possible, by stroke pathological type: ischaemic stroke, primary intracerebral haemorrhage, and subarachnoid haemorrhage. This Review shows a divergent, statistically significant trend in stroke incidence rates over the past four decades, with a 42% decrease in stroke incidence in high-income countries and a greater than 100% increase in stroke incidence in low to middle income countries. In 2000-08, the overall stroke incidence rates in low to middle income countries have, for the first time, exceeded the level of stroke incidence seen in high-income countries, by 20%. The time to decide whether or not stroke is an issue that should be on the governmental agenda in low to middle income countries has now passed. Now is the time for action. 10.1016/S1474-4422(09)70025-0
    Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Mendelow A David,Gregson Barbara A,Rowan Elise N,Murray Gordon D,Gholkar Anil,Mitchell Patrick M, Lancet (London, England) BACKGROUND:The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients. METHODS:In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967. FINDINGS:307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI -4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367). INTERPRETATION:The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage. FUNDING:UK Medical Research Council. 10.1016/S0140-6736(13)60986-1
    White Matter Injury after Intracerebral Hemorrhage: Pathophysiology and Therapeutic Strategies. Tao Chuanyuan,Hu Xin,Li Hao,You Chao Frontiers in human neuroscience Intracerebral hemorrhage (ICH) accounts for 10%-30% of all types of stroke. Bleeding within the brain parenchyma causes gray matter (GM) destruction as well as proximal or distal white matter (WM) injury (WMI) due to complex pathophysiological mechanisms. Because WM has a distinct cellular architecture, blood supply pattern and corresponding function, and its response to stroke may vary from that of GM, a better understanding of the characteristics of WMI following ICH is essential and may shed new light on treatment options. Current evidence using histological, radiological and chemical biomarkers clearly confirms the spatio-temporal distribution of WMI post- ICH. Although certain types of pathological damage such as inflammatory, oxidative and neuro-excitotoxic injury to WM have been identified, the exact molecular mechanisms remain unclear. In this review article, we briefly describe the constitution and physiological function of brain WM, summarize evidence regarding WMI, and focus on the underlying pathophysiological mechanisms and therapeutic strategies. 10.3389/fnhum.2017.00422
    Targeting miR-124/Ferroportin signaling ameliorated neuronal cell death through inhibiting apoptosis and ferroptosis in aged intracerebral hemorrhage murine model. Bao Wen-Dai,Zhou Xiao-Ting,Zhou Lan-Ting,Wang Fudi,Yin Xiaoping,Lu Youming,Zhu Ling-Qiang,Liu Dan Aging cell Incidence of intracerebral hemorrhage (ICH) and brain iron accumulation increases with age. Excess iron accumulation in brain tissues post-ICH induces oxidative stress and neuronal damage. However, the mechanisms underlying iron deregulation in ICH, especially in the aged ICH model have not been well elucidated. Ferroportin1 (Fpn) is the only identified nonheme iron exporter in mammals to date. In our study, we reported that Fpn was significantly upregulated in perihematomal brain tissues of both aged ICH patients and mouse model. Fpn deficiency induced by injecting an adeno-associated virus (AAV) overexpressing cre recombinase into aged Fpn-floxed mice significantly worsened the symptoms post-ICH, including hematoma volume, cell apoptosis, iron accumulation, and neurologic dysfunction. Meanwhile, aged mice pretreated with a virus overexpressing Fpn showed significant improvement of these symptoms. Additionally, based on prediction of website tools, expression level of potential miRNAs in ICH tissues and results of luciferase reporter assays, miR-124 was identified to regulate Fpn expression post-ICH. Higher serum miR-124 levels were correlated with poor neurologic scores of aged ICH patients. Administration of miR-124 antagomir enhanced Fpn expression and attenuated iron accumulation in aged mice model. Both apoptosis and ferroptosis, but not necroptosis, were regulated by miR-124/Fpn signaling manipulation. Our study demonstrated the critical role of miR-124/Fpn signaling in iron metabolism and neuronal death post-ICH in aged murine model. Thus, Fpn upregulation or miR-124 inhibition might be promising therapeutic approachs for this disease. 10.1111/acel.13235
    Neuroinflammation in intracerebral haemorrhage: immunotherapies with potential for translation. Xue Mengzhou,Yong V Wee The Lancet. Neurology Intracerebral haemorrhage is inadequately controlled by current treatments, requiring new solutions to improve the prognosis. Following the primary injury, a proinflammatory cascade in the perihaematomal region, composed of activated resident microglia and astrocytes and infiltrated leucocytes, propagates neural cell death. The protracted nature of neuroinflammation in intracerebral haemorrhage provides a window of opportunity for therapies to subdue the undesired consequences. In animal models and early clinical trials in intracerebral haemorrhage, several drugs have reduced detrimental neuroinflammation without substantial compromise of the beneficial reparative aspects of an inflammatory response. Potential strategies include controlling excessive harmful neuroinflammation with minocycline, sphingosine-1-phosphate receptor modulators, and statins after a brain haemorrhage. The quick initiation of these drugs, particularly in high systemic doses, could be key to counteracting the evolving secondary injury in people with intracerebral haemorrhage and provides a promising way in which the poor prognosis of intracerebral haemorrhage might one day be counteracted. 10.1016/S1474-4422(20)30364-1
    Advances in the management of intracerebral hemorrhage. Adeoye Opeolu,Broderick Joseph P Nature reviews. Neurology Intracerebral hemorrhage (ICH) is a major public-health problem worldwide. No proven treatments are available for this condition, which is associated with high rates of morbidity and mortality. Only 20% of individuals who survive ICH are independent at 6 months. Hypertension, cerebral amyloid angiopathy (CAA) and anticoagulation are known to be associated with such hemorrhages. No effective preventive therapies exist specifically for CAA-related ICH. The incidence of hypertension-related ICH might be decreasing in some populations with improvements in the treatment of hypertension; however, the incidence of anticoagulant-related ICH is increasing, as the use of anticoagulants rises. Many questions remain unanswered regarding the clinical management of ICH, although in the past 10 years completed medical and surgical clinical trials-examining hemostatic therapy, blood pressure control and/or hematoma evacuation-have refined our understanding of the goals of such management. Ongoing clinical trials, which have built on the lessons of past studies, hold promise for the development of effective, scientifically proven treatments for ICH. In this Review, we discuss clinical trials for ICH that have been completed in the past 10 years, the contributions of these studies to the clinical management of ICH, and the ongoing trials that might further improve clinical care. 10.1038/nrneurol.2010.146
    Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Hanley Daniel F,Thompson Richard E,Rosenblum Michael,Yenokyan Gayane,Lane Karen,McBee Nichol,Mayo Steven W,Bistran-Hall Amanda J,Gandhi Dheeraj,Mould W Andrew,Ullman Natalie,Ali Hasan,Carhuapoma J Ricardo,Kase Carlos S,Lees Kennedy R,Dawson Jesse,Wilson Alastair,Betz Joshua F,Sugar Elizabeth A,Hao Yi,Avadhani Radhika,Caron Jean-Louis,Harrigan Mark R,Carlson Andrew P,Bulters Diederik,LeDoux David,Huang Judy,Cobb Cully,Gupta Gaurav,Kitagawa Ryan,Chicoine Michael R,Patel Hiren,Dodd Robert,Camarata Paul J,Wolfe Stacey,Stadnik Agnieszka,Money P Lynn,Mitchell Patrick,Sarabia Rosario,Harnof Sagi,Barzo Pal,Unterberg Andreas,Teitelbaum Jeanne S,Wang Weimin,Anderson Craig S,Mendelow A David,Gregson Barbara,Janis Scott,Vespa Paul,Ziai Wendy,Zuccarello Mario,Awad Issam A, Lancet (London, England) BACKGROUND:Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS:MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS:Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION:For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING:National Institute of Neurological Disorders and Stroke and Genentech. 10.1016/S0140-6736(19)30195-3
    White Matter Injury After Intracerebral Hemorrhage. Fu Xiongjie,Zhou Guoyang,Zhuang Jianfeng,Xu Chaoran,Zhou Hang,Peng Yucong,Cao Yang,Zeng Hanhai,Li Jianru,Yan Feng,Wang Lin,Chen Gao Frontiers in neurology Spontaneous intracerebral hemorrhage (ICH) accounts for 15% of all stroke cases. ICH is a devastating form of stroke associated with high morbidity, mortality, and disability. Preclinical studies have explored the mechanisms of neuronal death and gray matter damage after ICH. However, few studies have examined the development of white matter injury (WMI) following ICH. Research on WMI indicates that its pathophysiological presentation involves axonal damage, demyelination, and mature oligodendrocyte loss. However, the detailed relationship and mechanism between WMI and ICH remain unclear. Studies of other acute brain insults have indicated that WMI is strongly correlated with cognitive deficits, neurological deficits, and depression. The degree of WMI determines the short- and long-term prognosis of patients with ICH. This review demonstrates the structure and functions of the white matter in the healthy brain and discusses the pathophysiological mechanism of WMI following ICH. Our review reveals that the development of WMI after ICH is complex; therefore, comprehensive treatment is essential. Understanding the relationship between WMI and other brain cells may reveal therapeutic targets for the treatment of ICH. 10.3389/fneur.2021.562090
    Management of Intracerebral Hemorrhage: JACC Focus Seminar. Schrag Matthew,Kirshner Howard Journal of the American College of Cardiology Intracerebral hemorrhage (ICH) accounts for a disproportionate amount of stroke-related morbidity and mortality. Although chronic hypertension and cerebral amyloid angiopathy are the underlying cerebral vasculopathies accounting for the majority of ICH, there are a broad range of potential causes, and effective management requires accurate identification and treatment of the underlying mechanism of hemorrhage. Magnetic resonance imaging and vascular imaging techniques play a critical role in identifying disease mechanisms. Modern treatment of ICH focuses on rapid stabilization, often requiring urgent treatment of mass effect, aggressive blood pressure reduction and correction of contributing coagulopathies to achieve hemostasis. We discuss management of patients with ICH who continue to require long-term anticoagulation, the interaction of ICH with neurodegenerative diseases, and our approach to prognostication after ICH. We close this review with a discussion of novel medical and surgical approaches to ICH treatment that are being tested in clinical trials. 10.1016/j.jacc.2019.10.066
    Mincle is an ITAM-coupled activating receptor that senses damaged cells. Yamasaki Sho,Ishikawa Eri,Sakuma Machie,Hara Hiromitsu,Ogata Koji,Saito Takashi Nature immunology Macrophage-inducible C-type lectin (Mincle) is expressed mainly in macrophages and is induced after exposure to various stimuli and stresses. Here we show that Mincle selectively associated with the Fc receptor common gamma-chain and activated macrophages to produce inflammatory cytokines and chemokines. Mincle-expressing cells were activated in the presence of dead cells, and we identified SAP130, a component of small nuclear ribonucloprotein, as a Mincle ligand that is released from dead cells. To investigate whether Mincle is required for normal responses to cell death in vivo, we induced thymocyte death by irradiating mice and found that transient infiltration of neutrophils into the thymus could be blocked by injection of Mincle-specific antibody. Our results suggest that Mincle is a receptor that senses nonhomeostatic cell death and thereby induces the production of inflammatory cytokines to drive the infiltration of neutrophils into damaged tissue. 10.1038/ni.1651
    An atypical role for the myeloid receptor Mincle in central nervous system injury. Arumugam Thiruma V,Manzanero Silvia,Furtado Milena,Biggins Patrick J,Hsieh Yu-Hsuan,Gelderblom Mathias,MacDonald Kelli Pa,Salimova Ekaterina,Li Yu-I,Korn Othmar,Dewar Deborah,Macrae I Mhairi,Ashman Robert B,Tang Sung-Chun,Rosenthal Nadia A,Ruitenberg Marc J,Magnus Tim,Wells Christine A Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism The C-type lectin Mincle is implicated in innate immune responses to sterile inflammation, but its contribution to associated pathologies is not well understood. Herein, we show that Mincle exacerbates neuronal loss following ischemic but not traumatic spinal cord injury. Loss of Mincle was beneficial in a model of transient middle cerebral artery occlusion but did not alter outcomes following heart or gut ischemia. High functional scores in Mincle KO animals using the focal cerebral ischemia model were accompanied by reduced lesion size, fewer infiltrating leukocytes and less neutrophil-derived cytokine production than isogenic controls. Bone marrow chimera experiments revealed that the presence of Mincle in the central nervous system, rather than recruited immune cells, was the critical regulator of a poor outcome following transient middle cerebral artery occlusion. There was no evidence for a direct role for Mincle in microglia or neural activation, but expression in a subset of macrophages resident in the perivascular niche provided new clues on Mincle's role in ischemic stroke. 10.1177/0271678X16661201
    Involvement of Mincle and Syk in the changes to innate immunity after ischemic stroke. Suzuki Yukiya,Nakano Yusuke,Mishiro Keisuke,Takagi Toshinori,Tsuruma Kazuhiro,Nakamura Mitsuhiro,Yoshimura Shinichi,Shimazawa Masamitsu,Hara Hideaki Scientific reports Accumulating evidence shows that post-ischemic inflammation originated by Toll-like receptors (TLR) plays critical roles in ischemic stroke. However, the functions of other innate immune receptors are poorly understood in cerebral ischemia. Macrophage-inducible C-type lectin, Mincle, is one of the innate immune receptor C-type lectin-like receptor (CLR) to response against dying cells. In the present study, we showed that Mincle, its ligand SAP130, and its downstream phospho-Syk/Syk were upregulated after ischemia, and that Mincle is expressed in immune and non-immune cells in the ischemic brains of mice and human. We treated mice with piceatannol, a Syk inhibitor, and consequently the infarct volume and swelling were suppressed by piceatannol. The levels of phospho-Syk, MMP9 and ICAM-1 were downregulated, and the level of Claudin5 was uplegurated in piceatannol-treated groups. These data indicate that innate immune system, such as Mincle and Syk plays a pivotal role in the pathogenesis after the ischemia and reperfusion. 10.1038/srep03177
    Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Gross Olaf,Poeck Hendrik,Bscheider Michael,Dostert Catherine,Hannesschläger Nicole,Endres Stefan,Hartmann Gunther,Tardivel Aubry,Schweighoffer Edina,Tybulewicz Victor,Mocsai Attila,Tschopp Jürg,Ruland Jürgen Nature Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1beta (IL-1beta) is a key pro-inflammatory factor in innate antifungal immunity. The mechanism by which the mammalian immune system regulates IL-1beta production after fungal recognition is unclear. Two signals are generally required for IL-1beta production: an NF-kappaB-dependent signal that induces the synthesis of pro-IL-1beta (p35), and a second signal that triggers proteolytic pro-IL-1beta processing to produce bioactive IL-1beta (p17) via Caspase-1-containing multiprotein complexes called inflammasomes. Here we demonstrate that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL-1beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1beta synthesis selectively uses the Card9 pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmalogical inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (also known as NALP3) was identified as the critical NOD-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (Pycard) for Caspase-1 (Casp1) activation and pro-IL-1beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, we show that Nlrp3-deficient mice are hypersusceptible to Candida albicans infection. Thus, our results demonstrate the molecular basis for IL-1beta production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo. 10.1038/nature07965
    An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells. Yasukawa Shinsuke,Miyazaki Yoshiyuki,Yoshii Chika,Nakaya Mako,Ozaki Naoko,Toda Shuji,Kuroda Etsushi,Ishibashi Ken-ichi,Yasuda Tomoharu,Natsuaki Yohei,Mi-ichi Fumika,Iizasa Ei'ichi,Nakahara Takeshi,Yamazaki Masanori,Kabashima Kenji,Iwakura Yoichiro,Takai Toshiyuki,Saito Takashi,Kurosaki Tomohiro,Malissen Bernard,Ohno Naohito,Furue Masutaka,Yoshida Hiroki,Hara Hiromitsu Nature communications A variety of reactive organic compounds, called haptens, can cause allergic contact dermatitis. However, the innate immune mechanisms by which haptens stimulate dendritic cells (DCs) to sensitize T cells remain unclear. Here we show that the coupling of ITAM-Syk-CARD9 signalling to interleukin-1 (IL-1) secretion in DCs is crucial for allergic sensitization to haptens. Both MyD88 and Caspase recruitment domain-containing protein 9 (CARD9) signalling are required for contact hypersensitivity (CHS). Naïve T cells require signals received through IL-1R1-MyD88 for effector differentiation, whereas DCs require CARD9 and spleen tyrosine kinase (Syk) signalling for hapten-induced IL-1α/β secretion and their ability to prime T cells. DC-specific deletion of CARD9, DAP12, Syk or NLRP3, but not MyD88, is sufficient to abolish CHS. All tested haptens, but not irritants, can induce Syk activation, leading to both the CARD9/BCL10-dependent pro-IL-1 synthesis (signal1) and reactive oxygen species-mediated NLRP3 inflammasome activation (signal2), required for IL-1 secretion. These data unveil an innate immune mechanism crucial for allergic contact sensitization to chemical compounds. 10.1038/ncomms4755
    Syk kinase-coupled C-type lectin receptors engage protein kinase C-δ to elicit Card9 adaptor-mediated innate immunity. Strasser Dominikus,Neumann Konstantin,Bergmann Hanna,Marakalala Mohlopheni J,Guler Reto,Rojowska Anna,Hopfner Karl-Peter,Brombacher Frank,Urlaub Henning,Baier Gottfried,Brown Gordon D,Leitges Michael,Ruland Jürgen Immunity C-type lectin receptors (CLRs) that couple with the kinase Syk are major pattern recognition receptors for the activation of innate immunity and host defense. CLRs recognize fungi and other forms of microbial or sterile danger, and they induce inflammatory responses through the adaptor protein Card9. The mechanisms relaying CLR proximal signals to the core Card9 module are unknown. Here we demonstrated that protein kinase C-δ (PKCδ) was activated upon Dectin-1-Syk signaling, mediated phosphorylation of Card9 at Thr231, and was responsible for Card9-Bcl10 complex assembly and canonical NF-κB control. Prkcd(-/-) dendritic cells, but not those lacking PKCα, PKCβ, or PKCθ, were defective in innate responses to Dectin-1, Dectin-2, or Mincle stimulation. Moreover, Candida albicans-induced cytokine production was blocked in Prkcd(-/-) cells, and Prkcd(-/-) mice were highly susceptible to fungal infection. Thus, PKCδ is an essential link between Syk activation and Card9 signaling for CLR-mediated innate immunity and host protection. 10.1016/j.immuni.2011.11.015
    Inflammatory cytokine cascade released by leukocytes in cerebrospinal fluid after subarachnoid hemorrhage. Takizawa T,Tada T,Kitazawa K,Tanaka Y,Hongo K,Kameko M,Uemura K I Neurological research Subarachnoid hemorrhage (SAH) elicits an inflammatory response in the subarachnoid space, which is mediated by the release of various cytokines. To assess their involvement in post-hemorrhagic complications, we determined the source and time-course of the release of inflammatory cytokines and acute-phase proteins in cerebrospinal fluid (CSF) following SAH. Concentrations of interleukin (IL)- 1beta, IL-6, transforming growth factor-beta1 (TGF-beta1) and C-reactive protein (CRP) in CSF of 36 patients with SAH were measured by enzyme-linked immunoabsorbent assay (ELISA). Floating cells collected from the CSF were centrifuged four to six days after SAH, and examined immunohistochemically. Intracellular IL-1beta and IL-6 were examined by flow cytometric analysis. The molecular weight of TGF-beta1 in CSF of 30 patients was examined by Western blot analysis. The TGF-beta1 levels of patients who had undergone ventriculoperitoneal (VP) shunt (n = 19) was significantly higher than nonshunt group (n = 16). The CRP levels of VP shunt group was significantly higher than nonshunt group. IL-6 concentration was maximal within day 0-1 and it was secreted by neutrophils and monocytes. ELISA showed consistently low levels of IL-1beta, whereas a proportion of monocytes and lymphcytes were IL- 1beta-positive by flow cytometric analysis. TGF-beta1 levels were also maximal on day 0-1 according to ELISA, although it tended to be in the inactive form derived from platelets. A 25 kDa band of TGF-1 was detectable for at least 13 days after SAH, which may have been secreted in part by neutrophils and monocytes. CRP levels in CSF peaked on day 2-3. The present results suggest that leukocytes induced by SAH play an important role in post-hemorrhagic inflammation in the subarachnoid space by releasing IL-6 and TGF-beta1. The CRP and TGF-beta1 levels in CSF are strongly concerned with communicating hydrocephalus after SAH. 10.1179/016164101101199243
    Mincle and human B cell function. Kawata Kazuhito,Illarionov Petr,Yang Guo-Xiang,Kenny Thomas P,Zhang Weici,Tsuda Masanobu,Ando Yugo,Leung Patrick S C,Ansari Aftab A,Gershwin M Eric Journal of autoimmunity C-type lectin receptors are pattern recognition receptors that are critical for autoimmunity and the immune response. Mincle is a C-type lectin receptor expressed by a variety of antigen presenting cells including macrophages, neutrophils, dendritic cells and B cells; a variety of stimuli including stress are known to induce the expression of Mincle. Mincle is an FcRγ-associated activation receptor that senses damaged cells and upon ligation induces activated macrophages to produce inflammatory cytokines. Recently, while several studies have reported that Mincle plays an important role in macrophage responses to fungal infection its function on B cells remains to be defined. In efforts to elucidate the function of Mincle expressed by B cells, we studied the expression of Mincle on subsets of B cells and analyzed cytokines and synthesized immunoglobulin upon ligation of Mincle. The expression of Mincle on CD27-CD19(+) naïve B cells is significantly higher than CD27 + CD19(+) memory B cells. The stimulation of TLR9 ligand induced Mincle expression on B cells. Furthermore, co-stimulation of TLR9 and Mincle ligand reduced IgG and IgA production from B cells without a significant change in the inflammatory cytokines TNF-α, IL-6, IL-8 and IL-10. Our data identifies Mincle as a potentially critical player in human B cell responses. 10.1016/j.jaut.2012.04.004
    Mast cells generated from patients with atopic eczema have enhanced levels of granule mediators and an impaired Dectin-1 expression. Ribbing C,Engblom C,Lappalainen J,Lindstedt K,Kovanen P T,Karlsson M A,Lundeberg L,Johansson C,Nilsson G,Lunderius-Andersson C,Scheynius A Allergy BACKGROUND:The disrupted skin barrier of patients with atopic eczema (AE) might facilitate contact between mast cells (MCs) in the skin and environmental triggers of the disease. One such trigger is the skin-colonizing yeast Malassezia sympodialis (M. sympodialis). In this study, we investigated the interaction of MC with M. sympodialis. METHODS:Mast cells were generated from peripheral blood CD34(+) progenitor cells of healthy controls (HC) and M. sympodialis-sensitized AE patients. Biopsy specimens were taken from HC and lesional AE skin for immunohistological stainings. RESULTS:The progenitor-derived MCs expressed the macrophage-inducible C-type lectin receptor Mincle, and exposure of these cells to M. sympodialis induced up-regulation of the mRNA expression of Mincle. Furthermore, we demonstrate that, when compared to HC, the progenitor-derived MCs from AE patients (i) contain more intrinsic granule mediators such as histamine, (ii) exhibit enhanced IL-6 release in response to M. sympodialis exposure, and (iii) have an impaired up-regulation of the fungal recognition receptor Dectin-1. In addition, analysis of skin sections from HC and AE patients revealed MCs as the predominant Dectin-1-expressing cell type in the skin. CONCLUSION:Our data indicate that progenitor-derived MCs from AE patients differ from those from HC. Further investigations with skin-derived MCs are necessary to confirm the observed differences which could provide new insights into the pathogenic mechanisms underlying AE. 10.1111/j.1398-9995.2010.02437.x
    Innate immune response gene expression profiles of N9 microglia are pathogen-type specific. McKimmie Clive S,Roy Douglas,Forster Thorsten,Fazakerley John K Journal of neuroimmunology Glial cells, particularly microglia, are thought to play a pivotal role in initiating and guiding innate immune responses to CNS infections and in perpetuating inflammation and pathology in CNS diseases such as multiple sclerosis and Alzheimer's disease. We describe here the development and use of a new microarray designed to specifically profile transcript expression of innate immunity genes. Microarray analysis validated by quantitative PCR demonstrated an extensive range of pattern recognition receptor gene expression in resting N9 microglia, including Toll-like receptors, scavenger receptors and lectins. Stimulation with LPS or infection with virus modulated pattern recognition receptor, cytokine, chemokine and other innate immune transcripts in a distinct and stimulus-specific manner. This study demonstrates that a single glial cell phenotype has an innate capability to detect infection, determine its form and generate specific responses. 10.1016/j.jneuroim.2006.03.012
    Identification of lectin-like receptors expressed by antigen presenting cells and neutrophils and their mapping to a novel gene complex. Flornes Line Mari,Bryceson Yenan T,Spurkland Anne,Lorentzen Johnny C,Dissen Erik,Fossum Sigbjørn Immunogenetics In an experimental rat model, we recently mapped an arthritis susceptibility locus to the distal part of Chromosome 4 containing genes predicted to encode C-type lectin superfamily (CLSF) receptors. Here we report the cDNA cloning and positional arrangement of these receptor genes, which represent rat orthologues to human Mincle and DCIR and to mouse MCL and Dectin-2, as well as four novel receptors DCIR2, DCIR3, DCIR4 and DCAR1, not previously reported in other species. We furthermore report the cDNA cloning of human Dectin-2 and MCL, and of the mouse orthologues to the novel rat receptors. Similar to the killer-cell lectin-like receptors (KLR) some of these receptors exhibit structural features suggesting that they regulate leukocyte reactivity; e.g., human DCIR and rodent DCIR1 and DCIR2 carry an immunoreceptor tyrosine-based inhibitory motif (ITIM), predicting inhibitory function, and conversely, in all three species Mincle has a positively charged amino acid in the transmembrane region, suggesting activating function. Sequence comparisons show that the receptors form a discrete family, more closely related to group II CLSF receptors than to the group V KLR. Their distance to the KLR is underscored by their preservation of evolutionary conserved calcium/saccharide binding residues, present in group II and lacking in group V CLSF and their cellular expression patterns, with most of the genes preferentially expressed by professional antigen-presenting cells (dendritic cells, macrophages and B cells) and neutrophils. In all three species, the genes map together, forming an evolutionary conserved gene complex, which we call the antigen presenting lectin-like receptor complex (APLEC). 10.1007/s00251-004-0714-x
    Minocycline-induced attenuation of iron overload and brain injury after experimental intracerebral hemorrhage. Zhao Fan,Hua Ya,He Yangdong,Keep Richard F,Xi Guohua Stroke BACKGROUND AND PURPOSE:Brain iron overload plays a detrimental role in brain injury after intracerebral hemorrhage (ICH). A recent study found that minocycline acts as an iron chelator and reduces iron-induced neuronal death in vitro. The present study investigated if minocycline reduces iron overload after ICH and iron-induced brain injury in vivo. METHODS:This study was divided into 4 parts: (1) rats with different sizes of ICH were euthanized 3 days later for serum total iron and brain edema determination; (2) rats had an ICH treated with minocycline or vehicle. Serum iron, brain iron, and brain iron handling proteins were measured; (3) rats had an intracaudate injection of saline, iron, iron+minocycline, or iron+macrophage/microglia inhibitory factor and were used for brain edema and neuronal death measurements; and (4) rats had an intracaudate injection of iron and were treated with minocycline. The brains were used for edema measurement. RESULTS:After ICH, serum total iron and brain nonheme iron increased and these changes were reduced by minocycline treatment. Minocycline also reduced ICH-induced upregulation of brain iron handling proteins and neuronal death. Intracaudate injection of iron caused brain edema, blood-brain barrier leakage, and brain cell death, all of which were significantly reduced by coinjection with minocycline. CONCLUSIONS:The current study found that minocycline reduces iron overload after ICH and iron-induced brain injury. It is also well known minocycline is an inhibitor of microglial activation. Minocycline may be very useful for patients with ICH because both iron accumulation and microglia activation contribute to brain damage after ICH. 10.1161/STROKEAHA.111.623926
    Inflammation after intracerebral hemorrhage. Wang Jian,Doré Sylvain Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Intracerebral hemorrhage (ICH) is a devastating clinical event without effective therapies. Increasing evidence suggests that inflammatory mechanisms are involved in the progression of ICH-induced brain injury. Inflammation is mediated by cellular components, such as leukocytes and microglia, and molecular components, including prostaglandins, chemokines, cytokines, extracellular proteases, and reactive oxygen species. Better understanding of the role of the ICH-induced inflammatory response and its potential for modulation might have profound implications for patient treatment. In this review, a summary of the available literature on the inflammatory responses after ICH is presented along with discussion of some of the emerging opportunities for potential therapeutic strategies. In the near future, additional strategies that target inflammation could offer exciting new promise in the therapeutic approach to ICH. 10.1038/sj.jcbfm.9600403
    Human albumin attenuates excessive innate immunity via inhibition of microglial Mincle/Syk signaling in subarachnoid hemorrhage. Xie Yi,Guo Hongquan,Wang Liumin,Xu Lili,Zhang Xiaohao,Yu Linjie,Liu Qian,Li Yunzi,Zhao Nana,Zhao Nan,Ye Ruidong,Liu Xinfeng Brain, behavior, and immunity Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke. Microglial macrophage-inducible C-type lectin (Mincle) receptor launches microglial innate immunity after SAH, and thereby achieves a key step of early cerebral injury in SAH. We previously revealed albumin could improve long-term neurological outcomes after SAH. In this study, we examined the role of microglia-mediated innate immunity in the salutary effects of albumin. SAH was induced by endovascular perforation in rats. We found that albumin can significantly mitigate early neurovascular dysfunction of SAH rats. Albumin administration resulted in reduced Iba-1 and CD68 staining in cortex. Markers of microglia M1 polarization (iNOS, IL-1β, CD16, and CD32) were remarkably suppressed. Neutrophil invasion was inhibited as chemokines (MCP-1, CINC-1, and CXCL-2) mRNA levels, myeloperoxidase (MPO) and intracellular adhesion molecule-1 (ICAM-1) expressions were decreased. Mechanistically, albumin bound with microglial Mincle receptor, and retarded Mincle/Syk/IL-1β signaling in ipsilateral hemisphere subjected to SAH. In the cultured BV-2 microglial cells, we found Mincle and its ligand SAP130 mediate the cross-talk between neuronal necroptosis and microglial immunity response following SAH-related injury. Albumin could attenuate SAP130-induced Mincle upregulation and subsequent microglial inflammatory responses. The anti-inflammation effect of albumin was similar to the effect of genetic knockdown of Mincle. This effect may be attributed to a direct association between albumin and Mincle. The interaction also yielded a depression in the initiation of Mincle/Syk/IL-1β pathway. In conclusion, our results indicate that albumin can ameliorate innate immune responses after SAH. This anti-inflammatory action may be through direct restraining microglial Mincle receptor. 10.1016/j.bbi.2016.11.004
    Macrophage-Inducible C-Type Lectin/Spleen Tyrosine Kinase Signaling Pathway Contributes to Neuroinflammation After Subarachnoid Hemorrhage in Rats. He Yue,Xu Liang,Li Bo,Guo Zhen-Ni,Hu Qin,Guo Zongduo,Tang Junjia,Chen Yujie,Zhang Yang,Tang Jiping,Zhang John H Stroke BACKGROUND AND PURPOSE:Macrophage-inducible C-type lectin (Mincle, CLEC4E) receptor is reported involved in neuroinflammation in cerebral ischemia and traumatic brain injury. This study was designed to investigate the role of Mincle and its downstream spleen tyrosine kinase (Syk) signal pathway in early brain injury after subarachnoid hemorrhage (SAH) in a rat model. METHODS:Two hundred fifteen male Sprague-Dawley rats (280-320 g) were subjected to endovascular perforation model of SAH. SAH grade, neurological score, and brain water content were measured at 24 hours after SAH. Mincle/Syk, as well as CARD9 (a member of the caspase-associated recruitment domain [CARD], involved in innate immune response), interleukin-1β,and myeloperoxidase expressions were analyzed by Western blot at 24 hours after SAH. Specific cell types that expressed Mincle were detected with double immunofluorescence staining. Mincle small interfering RNA, recombinant SAP130, and a selective Syk phosphorylation inhibitor piceatannol were used for intervention. RESULTS:Brain water content increased and neurological functions decreased in rats after SAH. The expression of SAP130, Mincle, Syk, and p-Syk increased at 12 hours and peaked at 24 hours after SAH. Mincle small interfering RNA reduced interleukin-1β and infiltration of myeloperoxidase positive cells, decreased brain water content, and improved neurological functions at 24 hours after SAH. Recombinant SAP130 upregulated the expression of p-Syk and CARD9 and increased the levels of interleukin-1β and myeloperoxidase, even though it did not increase brain water content nor it deteriorated neurological function at 24 hours after SAH. Syk inhibitor piceatannol reduced brain edema at 24 hours after SAH. CONCLUSION:Mincle/Syk is involved in early brain injury after SAH, and they may serve as new targets for therapeutic intervention. 10.1161/STROKEAHA.115.010088