Abstract TP111: Haptoglobin Improves Intracerebral Hemorrhage Outcomes by Modulating Angiogenic Responses

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Jenna Leclerc ◽  
Tina Esfandiary ◽  
Sylvain Dore
Keyword(s):  
Intracerebral Hemorrhage ◽  
Tissue Repair ◽  
Autologous Blood ◽  
Healing Process ◽  
Acute Injury ◽  
Neurological Deficits ◽  
Lesion Volume ◽  
Oxidative Potential ◽  
Ambulatory Ability ◽  
The Brain

Intracerebral hemorrhage (ICH) most often occurs spontaneously and is one of the most devastating stroke subtypes. Following ICH, toxic blood components must be cleared from the brain as part of the tissue repair/scar formation healing process. Angiogenesis is a key physiologic mechanism that facilitates tissue repair following acute injury, but must be tightly regulated to prevent excessive activity and deleterious consequences. After ICH, regulation of angiogenesis within the appropriate range in injured brain regions would allow for delivery of glucose and oxygen to support the energy-requiring reparative processes and facilitate the necessary entry of peripheral cells involved. Haptoglobin (Hp) is an acute phase protein that binds extracorpuscular hemoglobin, thereby directly reducing its oxidative potential, and Hp has also been shown to have potent angiogenic, vasculogenic, and wound healing properties. Using the autologous blood model of ICH, we have shown that Hp overexpression significantly improves ICH outcomes and reduces oxidative processes. Here, we aimed to confirm our previous results and further characterize the mechanisms by which Hp exerts these neuroprotective effects. Hp was overexpressed in the brain using adeno-associated viral vectors and ICH was induced using the collagenase-induced spontaneous bleeding model, which is accompanied by clinically relevant intraventricular hemorrhage. In line with our previous study, Hp-overexpressing mice demonstrate significantly smaller lesion volumes (p<0.01) and less residual blood (p<0.05). This reduced ICH-induced brain injury is accompanied by trends towards improved ambulatory ability and less focal neurological deficits at 72h post-ICH (p<0.07). Hp-overexpressing mice have significantly reduced PECAM-1 expression and tend to have less VEGF immunoreactivity. After correcting for lesion volume, Hp-overexpressing mice retain the decreased PECAM-1 expression, but VEGF expression is increased, collectively suggesting a direct role of Hp in positively modulating angiogenesis after ICH. Hp therapy could represent a new treatment strategy for ICH through a multifactorial mechanism that includes the modulation of important angiogenic processes.

scholarly journals MSC Secretome as a Promising Tool for Neuroprotection and Neuroregeneration in a Model of Intracerebral Hemorrhage

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2031
Author(s):  
Maxim Karagyaur ◽  
Stalik Dzhauari ◽  
Nataliya Basalova ◽  
Natalia Aleksandrushkina ◽  
Georgy Sagaradze ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Neurological Outcome ◽  
Multipotent Mesenchymal Stromal Cells ◽  
Lesion Volume ◽  
Therapeutic Approaches ◽  
Beneficial Effects ◽  
Tissue Repair And Regeneration ◽  
Promising Tool ◽  
Neurologic Disorders ◽  
The Brain

Multipotent mesenchymal stromal cells (MSCs) are considered to be critical contributors to injured tissue repair and regeneration, and MSC-based therapeutic approaches have been applied to many peripheral and central neurologic disorders. It has been demonstrated that the beneficial effects of MSC are mainly mediated by the components of their secretome. In the current study, we have explored the neuroprotective potential of the MSC secretome in a rat model of intracerebral hemorrhage and shown that a 10-fold concentrated secretome of human MSC and its combination with the brain-derived neurotrophic factor (BDNF) provided a better survival and neurological outcome of rats within 14 days of intracerebral hemorrhage compared to the negative (non-treated) and positive (BDNF) control groups. We found that it was due to the ability of MSC secretome to stimulate neuron survival under conditions of glutamate-induced neurotoxicity. However, the lesion volume did not shrink in these rats, and this also correlated with prominent microglia activation. We hypothesize that this could be caused by the species-specificity of the used MSC secretome and provide evidence to confirm this. Thus, we have found that allogenic rat MSC secretome was more effective than xenogenic human MSC secretome in the rat intracerebral hemorrhage model: it reduced the volume of the lesion and promoted excellent survival and neurological outcome of the treated rats.

scholarly journals Leukocyte dynamics after intracerebral hemorrhage in a living patient reveal rapid adaptations to tissue milieu

2020 ◽  
Author(s):  
Brittany A. Goods ◽  
Michael H. Askenase ◽  
Erica Markarian ◽  
Hannah E. Beatty ◽  
Riley Drake ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Single Cell ◽  
Brain Tissue ◽  
Cellular Response ◽  
Tissue Injury ◽  
Brain Inflammation ◽  
Therapeutic Interventions ◽  
Acute Injury ◽  
The Brain ◽  
Over Time

ABSTRACTIntracerebral hemorrhage (ICH) is a devastating form of stroke with a high mortality rate and few treatment options. Discovery of therapeutic interventions has been slow given the challenges associated with studying acute injury, particularly over time, in the human brain. Inflammation induced by exposure of brain tissue to blood appears to be a major part of brain tissue injury. Here we longitudinally profiled blood and cerebral hematoma effluent from a patient enrolled in the Minimally Invasive Surgery with Thrombolysis in Intracerebral Haemorrhage Evacuation (MISTIEIII) trial, offering a rare window into the local and systemic immune responses to acute brain injury. Using single-cell RNA-sequencing, we characterized the local cellular response during ICH in the brain of a living patient at single-cell resolution for the first time. Our analysis revealed rapid shifts in the activation states of myeloid and T cells in the brain over time, suggesting that leukocyte responses are dynamically reshaped by the hematoma microenvironment. Interestingly, the patient had an asymptomatic re-bleed (second local exposure to blood) that our transcriptional data indicated occurred more than 30 hours prior to detection by CT scan. This case highlights the rapid immune dynamics in the brain after ICH and suggests that sensitive methods like scRNA-seq can inform our understanding of complex intracerebral events.

scholarly journals Butin attenuates brain edema in a rat model of intracerebral hemorrhage by anti inflammatory pathway

2018 ◽  
Vol 9 (1) ◽  
pp. 7-12 ◽  
Author(s):  
Peiyu Li ◽  
Cheng Jiwu
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Treated Group ◽  
Control Group ◽  
Lesion Volume ◽  
Dependent Manner ◽  
Neurological Score ◽  
Factor Α ◽  
The Brain ◽  
Brain Tissues

Abstract Background This study evaluates the effect of butin against brain edema in intracerebral hemorrhage (ICH). Methodology ICH was induced by injecting bacterial collagenase in the brain and all the animals were separated into four groups such as control group, ICH group treated with vehicle, Butin 25 and 50 mg/kg group receives butin (25 and 50 mg/kg, i.p.)60 min after the induction of ICH in all animals. One day after neurological score, hemorrhagic injury and expressions of protein responsible for apoptosis and inflammatory cytokines were assessed in the brain tissue of ICH rats. Result Neurological scoring significantly increased and hemorrhagic lesion volume decreased in butin treated group of rats compared to ICH group. However, treatment with butin significantly decreases the ratio of Bax/Bcl-2 and protein expression of Cleaved caspase-3 than ICH group in dose dependent manner. Level of inflammatory mediators such as tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6) in the brain tissues were significantly decreased in the butin treated group than ICH group. In addition butin attenuates the altered signaling pathway of NF-κB in the brain tissues of ICH rats. Conclusion Our study concludes that butin attenuates the altered behavior and neuronal condition in ICH rats by reducing apoptosis and inflammatory response.

scholarly journals IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage

Stroke ◽  
2020 ◽  
Vol 51 (3) ◽  
pp. 967-974 ◽  
Author(s):  
Samuel X. Shi ◽  
Yu-Jing Li ◽  
Kaibin Shi ◽  
Kristofer Wood ◽  
Andrew F. Ducruet ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Autologous Blood ◽  
Brain Slices ◽  
Neurological Deficits ◽  
Transgenic Mouse Line ◽  
Il Interleukin ◽  
Targeted Expression ◽  
Interleukin 15

Background and Purpose— Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods— Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15 tg ). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results— In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15 tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15 tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1β, and TNF-α is markedly increased in GFAP-IL-15 tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15 tg mice. Conclusions— Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.

Abstract TP348: Quantitative Serial Neuroimaging of Iron in the Intracerebral Hemorrhage Pig Model

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Muhammad E Haque ◽  
Refaat E Gabr ◽  
Xiurong Zhao ◽  
Khader M Hasan ◽  
Ponnada A Narayana ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Autologous Blood ◽  
Iron Concentration ◽  
Susceptibility Mapping ◽  
Pig Model ◽  
Large Animal ◽  
Quantitative Susceptibility Mapping ◽  
Secondary Damage ◽  
Susceptibility Maps ◽  
The Brain

Objective: To serially quantify changes of iron concentration within hematomas in the intracerebral hemorrhage (ICH) pig model using non-invasive R2* and quantitative susceptibility mapping (QSM) MRI methods. Introduction: Hemolysis-related release of hemoglobin/heme/free iron after ICH causes cytotoxic injury. An accurate post hemorrhage assessment of iron would be valuable to develop strategies to prevent secondary damage. The T2* relaxation rate (R2* =1/T2*) on MRI depends on the regional oxy- versus deoxyhemoglobin. Post-ICH excess of deoxyhemoglobin has been applied as a quantitative marker to estimate iron in the brain. However, quantitative susceptibility mapping (QSM) is a new MRI technique that can quantify iron concentration within the hematoma by measuring induced magnetic susceptibility. Using R2* mapping and QSM in a large animal ICH model, we measured spatiotemporal changes in iron concentration in the brain. Methods: Lobar ICH was induced by infusion of 2.5 ml autologous blood in 8 Yorkshire pigs with average age/wt of 4-6wk/12.5±2.5kg. MRI was obtained at days 1 and 7. A 3D anatomical and multi-echo gradient echo images were obtained on a clinical 3.0 T Philips Ingenia MRI system. Parametric R2* and susceptibility maps were generated. Regions of interest were placed within hematoma and contralesional CSF. Results: R2* measurements in the hematoma at day 1 and day 7 were 41.3 ± 7.3 and 37.7 ± 7.7 s -1 , respectively, whereas the corresponding susceptibility measurements were 0.75± 0.3 and 0.70 ± 0.5 ppm. The CSF R2* were 5.53 ± 2.1 and 6.85 ± 2.4 s -1 , whereas susceptibility showed 0.06 ± 0.16 and 0.02 ± 0.03 ppm at the two time points. Both R2* and QSM showed no significant change in iron concentration within the hematoma ROI with p-value of 0.18 and 0.72 over a week. Absence of hyperintense regions remote from the hematoma in susceptibility maps suggested lack of diffuse iron deposition. Good correlation was observed between R2* and QSM (correlation coefficient 0.83 and 0.78 within hematoma, and -0.66 and -0.07 within CSF, at day 1 and 7, respectively). Conclusion: R2* and especially QSM, with their ability to provide quantitative iron content, are valuable tools to test new ICH treatments particularly targeting iron in this large animal model.

scholarly journals Bexarotene Enhances Macrophage Erythrophagocytosis and Hematoma Clearance in Experimental Intracerebral Hemorrhage

Stroke ◽  
2020 ◽  
Vol 51 (2) ◽  
pp. 612-618 ◽  
Author(s):  
Che-Feng Chang ◽  
Jordan Massey ◽  
Artem Osherov ◽  
Luís Henrique Angenendt da Costa ◽  
Lauren H. Sansing
Keyword(s):  
Intracerebral Hemorrhage ◽  
Functional Recovery ◽  
Autologous Blood ◽  
Neurological Deficits ◽  
Macrophage Phenotype ◽  
Timely Manner ◽  
Collagenase Injection ◽  
Necrosis Factor

Background and Purpose— Enhancement of erythrophagocytosis by macrophages in a timely manner can limit the toxic effects of erythrocyte metabolites and promote brain recovery after intracerebral hemorrhage (ICH). In the current study, we investigated the therapeutic effect of retinoid X receptor agonist, bexarotene, in facilitating erythrophagocytosis and neurobehavioral recovery in 2 mouse models of ICH. Methods— Bone marrow-derived macrophages and fluorescently labeled erythrocytes were used to study erythrophagocytosis in vitro with phenotypic changes quantified by gene expression. ICH was modeled in vivo using intrastriatal autologous blood and collagenase injection in mice with and without bexarotene treatment beginning 3 hours after ICH. In vivo phagocytosis, ability and hematoma clearance were evaluated by erythrophagocytosis assays, flow cytometry, and histological analysis. Neurological deficits and functional recovery were also quantified. Results— Bexarotene increased macrophage expression of phagocytosis receptors and erythrophagocytosis and reduced macrophage TNF (tumor necrosis factor) production in vitro. In vivo, bexarotene treatment enhanced erythrophagocytosis, reduced hematoma volume, and ultimately improved neurological recovery after ICH in 2 distinct models of ICH. Conclusions— Bexarotene administration is beneficial for recovery after ICH by enhancing hemorrhage phagocytosis, modulating macrophage phenotype, and improving functional recovery.

scholarly journals Intracerebral Hemorrhage: Blood Components and Neurotoxicity

2019 ◽  
Vol 9 (11) ◽  
pp. 316 ◽  
Author(s):  
Neha Madangarli ◽  
Frederick Bonsack ◽  
Rajaneekar Dasari ◽  
Sangeetha Sukumari–Ramesh
Keyword(s):  
Intracerebral Hemorrhage ◽  
Public Health Problem ◽  
Brain Parenchyma ◽  
Neurological Deficits ◽  
Blood Component ◽  
Major Public Health Problem ◽  
Blood Components ◽  
Secondary Brain Damage ◽  
Mortality And Morbidity ◽  
The Brain

Intracerebral hemorrhage (ICH) is a subtype of stroke which is associated with the highest mortality and morbidity rates of all strokes. Although it is a major public health problem, there is no effective treatment for ICH. As a consequence of ICH, various blood components accumulate in the brain parenchyma and are responsible for much of the secondary brain damage and ICH-induced neurological deficits. Therefore, the strategies that could attenuate the blood component-induced neurotoxicity and improve hematoma resolution are highly needed. The present article provides an overview of blood-induced brain injury after ICH and emphasizes the need to conduct further studies elucidating the mechanisms of hematoma resolution after ICH.

scholarly journals Minocycline promotes posthemorrhagic neurogenesis via M2 microglia polarization via upregulation of the TrkB/BDNF pathway in rats

2018 ◽  
Vol 120 (3) ◽  
pp. 1307-1317 ◽  
Author(s):  
Hongsheng Miao ◽  
Runming Li ◽  
Cong Han ◽  
Xiuzhen Lu ◽  
Hang Zhang
Keyword(s):  
Intracerebral Hemorrhage ◽  
Therapeutic Potential ◽  
Autologous Blood ◽  
Neurological Deficits ◽  
Neuroprotective Effects ◽  
Microglial Polarization ◽  
Arginase 1 ◽  
M2 Microglia ◽  
Microglia Polarization ◽  
Bdnf Pathway

Intracerebral hemorrhage (ICH) is a devastating disease worldwide with increasing mortality. The present study investigated whether minocycline was neuroprotective and induced M2 microglial polarization via upregulation of the TrkB/BDNF pathway after ICH. ICH was induced via injection of autologous blood into 150 Sprague-Dawley rats. A selective TrkB antagonist [N2–2-2-oxoazepan-3-yl amino] carbonyl phenyl benzo (b) thiophene-2-carboxamide (ANA 12)] and agonist [ N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC)] were used to investigate the mechanism of minocycline-induced neuroprotection. Minocycline improved ICH-induced neurological deficits and reduced M1 microglia marker protein (CD68, CD16) expression as well as M2 microglial polarization (CD206 and arginase 1 protein). Minocycline administration enhanced microglia-neuron cross talk and promoted the proliferation of neuronal progenitor cells, such as DCX- and Tuj-1-positive cells, 24 h after ICH. Minocycline also increased M2 microglia-derived brain-derived neurotrophic factors (BDNF) and the upstream TrkB pathway. ANA 12 reversed the neuroprotective effects of minocycline. HIOC exhibited the same effects as minocycline and accelerated neurogenesis after ICH. This study demonstrated for the first time that minocycline promoted M2 microglia polarization via upregulation of the TrkB/BDNF pathway and promoted neurogenesis after ICH. This study contributes to our understanding of the therapeutic potential of minocycline in ICH. NEW & NOTEWORTHY The present study gives several novel points: 1) Minocycline promotes neurogenesis after intracerebral hemorrhage in rats. 2) Minocycline induces activated M1 microglia into M2 neurotrophic phenotype. 3) M2 microglia secreting BDNF remodel the damaged neurocircuit.

scholarly journals Colony stimulating factor 1 receptor inhibition eliminates microglia and attenuates brain injury after intracerebral hemorrhage

2016 ◽  
Vol 37 (7) ◽  
pp. 2383-2395 ◽  
Author(s):  
Minshu Li ◽  
Zhiguo Li ◽  
Honglei Ren ◽  
Wei-Na Jin ◽  
Kristofer Wood ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Autologous Blood ◽  
Lesion Size ◽  
Experimental Models ◽  
Colony Stimulating Factor ◽  
Receptor Inhibition ◽  
Experimental Mouse ◽  
The Brain ◽  
Stimulating Factor ◽  
Blood Brain Barrier Integrity

Microglia are the first responders to intracerebral hemorrhage, but their precise role in intracerebral hemorrhage remains to be defined. Microglia are the only type of brain cells expressing the colony-stimulating factor 1 receptor, a key regulator for myeloid lineage cells. Here, we determined the effects of a colony-stimulating factor 1 receptor inhibitor (PLX3397) on microglia and the outcome in the context of experimental mouse intracerebral hemorrhage. We show that PLX3397 effectively depleted microglia, and the depletion of microglia was sustained after intracerebral hemorrhage. Importantly, colony-stimulating factor 1 receptor inhibition attenuated neurodeficits and brain edema in two experimental models of intracerebral hemorrhage induced by injection of collagenase or autologous blood. The benefit of colony-stimulating factor 1 receptor inhibition was associated with reduced leukocyte infiltration in the brain and improved blood–brain barrier integrity after intracerebral hemorrhage, and each observation was independent of lesion size or hematoma volume. These results demonstrate that suppression of colony-stimulating factor 1 receptor signaling ablates microglia and confers protection after intracerebral hemorrhage.

scholarly journals Mature Adult Mice With Exercise-Preconditioning Show Better Recovery After Intracerebral Hemorrhage

Stroke ◽  
2021 ◽  
Vol 52 (5) ◽  
pp. 1861-1865
Author(s):  
Keita Kinoshita ◽  
Gen Hamanaka ◽  
Ryo Ohtomo ◽  
Hajime Takase ◽  
Kelly K. Chung ◽  
...  
Keyword(s):  
Physical Exercise ◽  
Intracerebral Hemorrhage ◽  
Treadmill Exercise ◽  
Neurological Deficits ◽  
Multiple Time ◽  
Lesion Volume ◽  
Soluble Factors ◽  
Mature Adult ◽  
Adult Mice ◽  
Exercise Preconditioning

Background and Purpose: Physical exercise offers therapeutic potentials for several central nervous system disorders, including stroke and cardiovascular diseases. However, it is still mostly unknown whether and how exercise preconditioning affects the prognosis of intracerebral hemorrhage (ICH). In this study, we examined the effects of preconditioning on ICH pathology in mature adult mice using treadmill exercise. Methods: Male C57BL/6J (25-week old) mice were subjected to 6 weeks of treadmill exercise followed by ICH induction. Outcome measurements included various neurological function tests at multiple time points and the assessment of lesion volume at 8 days after ICH induction. In addition, plasma soluble factors and phagocytotic microglial numbers in the peri-lesion area were also measured to determine the mechanisms underlying the effects of exercise preconditioning. Results: The 6-week treadmill exercise preconditioning promoted recovery from ICH-induced neurological deficits in mice. In addition, mice with exercise preconditioning showed smaller lesion volumes and increased numbers of phagocytotic microglia. Furthermore, the levels of several soluble factors, including endostatin, IGFBP (insulin-like growth factor-binding protein)-2 and -3, MMP (matrix metallopeptidase)-9, osteopontin, and pentraxin-3, were increased in the plasma samples from ICH mice with exercise preconditioning compared with ICH mice without exercise. Conclusions: These results suggest that mice with exercise preconditioning may suffer less severe injury from hemorrhagic stroke, and therefore, a habit of physical exercise may improve brain health even in middle adulthood.

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