Search

Hematoma clearance is critical for mitigating intracerebral hemorrhage (ICH)-induced brain injury. Multinucleated giant cells (MGCs), a type of phagocyte, and the complement system may play a pivotal role in hematoma resolution, but whether the complement system regulates MGC formation after ICH remains unclear. The current study investigated the following: (1) the characteristics of MGC formation after ICH, (2) whether it was impacted by complement C3 deficiency in mice and (3) whether it also influenced hematoma degradation (hemosiderin formation). Young and aged male mice, young female mice and C3-deficient and -sufficient mice received a 30 μL injection of autologous whole blood into the right basal ganglia. Brain histology and immunohistochemistry were used to examine MGC formation on days 3 and 7. Hemosiderin deposition was examined by autofluorescence on day 28. Following ICH, MGCs were predominantly located in the peri-hematoma region exhibiting multiple nuclei and containing red blood cells or their metabolites. Aging was associated with a decrease in MGC formation after ICH, while sex showed no discernible effect. C3 deficiency reduced MGC formation and reduced hemosiderin formation. Peri-hematomal MGCs may play an important role in hematoma resolution. Understanding how aging and complement C3 impact MGCs may provide important insights into how to regulate hematoma resolution. [ABSTRACT FROM AUTHOR]

Both monocyte-derived macrophages (MDMs) and brain resident microglia participate in hematoma resolution after intracerebral hemorrhage (ICH). Here, we utilized a transgenic mouse line with enhanced green fluorescent protein (EGFP) labeled microglia (Tmem119-EGFP mice) combined with a F4/80 immunohistochemistry (a pan-macrophage marker) to visualize changes in MDMs and microglia after ICH. A murine model of ICH was used in which autologous blood was stereotactically injected into the right basal ganglia. The autologous blood was co-injected with CD47 blocking antibodies to enhance phagocytosis or clodronate liposomes for phagocyte depletion. In addition, Tmem119-EGFP mice were injected with the blood components peroxiredoxin 2 (Prx2) or thrombin. MDMs entered the brain and formed a peri-hematoma cell layer by day 3 after ICH and giant phagocytes engulfed red blood cells were found. CD47 blocking antibody increased the number of MDMs around and inside the hematoma and extended MDM phagocytic activity to day 7. Both MDMs and microglia could be diminished by clodronate liposomes. Intracerebral injection of Prx2 but not thrombin attracted MDMs into brain parenchyma. In conclusion, MDMs play an important role in phagocytosis after ICH which can be enhanced by CD47 blocking antibody, suggesting the modulation of MDMs after ICH could be a future therapeutic target. [ABSTRACT FROM AUTHOR]

Aims: Iron released from lysed red blood cells within the hematoma plays a role in intracerebral hemorrhage (ICH)‐related neurotoxicity. This study utilizes magnetic resonance imaging (MRI) to examine the time course, extent of erythrolysis, and its correlation with perihematomal iron accumulation and white matter loss. Methods: The feasibility of assessing proportional erythrolysis using T2* MRI was examined using pig blood phantoms with specified degrees of erythrolysis. Fifteen prospectively enrolled ICH patients had MRIs (3‐Tesla) at days 1–3, 14, and 30 (termed early, subacute, and late periods, respectively). Measurement was performed on T2*, 1/T2*, and fractional anisotropy (FA) maps. Results: Pig blood phantoms showed a linear relationship between 1/T2* signal and percent erythrolysis. MRI on patients showed an increase in erythrolysis within the hematoma between the early and subacute phases after ICH, almost completing by day 14. Although perihematomal iron overload (IO) correlated with the erythrolysis extent and hematoma volume at days 14 and 30, perihematomal white matter (WM) loss significantly correlated with both, only at day 14. Conclusion: MRI may reliably assess the portion of the hematoma that lyses over time after ICH. Perihematomal IO and WM loss correlate with both the erythrolysis extent and hematoma volume in the early and subacute periods following ICH. [ABSTRACT FROM AUTHOR]

Aims: Over the past two decades, animal intracerebral hemorrhage (ICH) model studies have indicated that iron, released after hemoglobin degradation, is neurotoxic. Iron phantom and animal experiments have shown that magnetic resonance imaging (MRI) relaxivity maps correlate with iron concentration. This study expands this into patients. Methods: Eighteen human subjects with ICH underwent MRI at 3, 14, and 30 days. R2* relaxivity maps were used to calculate perihematomal iron concentrations and T2 imaging to determine hematoma and edema volumes. Results: Perihematomal iron concentrations were increased at all three time points and decreased with distance from the hematoma. While perihematomal iron concentrations did not vary with hematoma size, the total iron overload (increased iron concentration x volume of affected tissue) did. Total iron overload correlated with edema volume. Conclusions: These results demonstrate the feasibility of measuring perihematomal iron in ICH patients which may be important for monitoring treatment strategies and assessing efficacy noninvasively. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage is associated with significant morbidity and mortality. Some clinical trials demonstrated a trend towards benefit with surgical evacuation of intracerebral hemorrhage, without strong statistically significant results. Subsequent studies focused on minimally invasive techniques. Improved outcomes were more likely with surgical reduction of intracerebral hemorrhage volume to ≤15 mL. Deferoxamine is currently being evaluated as a therapeutic tool in intracerebral hemorrhage with promising results. There continues to be a lack of level I evidence supporting medical and surgical tools for intracerebral hemorrhage evacuation. Could a combination of minimally invasive surgery with hematoma lysis and Deferoxamine result in more effective hematoma evacuation? [ABSTRACT FROM AUTHOR]

Vascular disruption is the underlying cause of cerebral hemorrhage, including intracerebral, subarachnoid and intraventricular hemorrhage. The disease etiology also involves cerebral hemorrhage-induced blood–brain barrier (BBB) disruption, which contributes an important component to brain injury after the initial cerebral hemorrhage. BBB loss drives vasogenic edema, allows leukocyte extravasation and may lead to the entry of potentially neurotoxic and vasoactive compounds into brain. This review summarizes current information on changes in brain endothelial junction proteins in response to cerebral hemorrhage (and clot-related factors), the mechanisms underlying junction modification and potential therapeutic targets to limit BBB disruption and, potentially, hemorrhage occurrence. It also addresses advances in the tools that are now available for assessing changes in junctions after cerebral hemorrhage and the potential importance of such junction changes. Recent studies suggest post-translational modification, conformational change and intracellular trafficking of junctional proteins may alter barrier properties. Understanding how cerebral hemorrhage alters BBB properties beyond changes in tight junction protein loss may provide important therapeutic insights to prevent BBB dysfunction and restore normal function. [ABSTRACT FROM AUTHOR]

Despite the absence of an intervention shown to improve outcomes in intracerebral hemorrhage, preclinical work has led to a greater understanding of the pathologic pathways of brain injury. Methods targeting hematoma clearance through both macroscopic (surgical) and microscopic (endogenous phagocytosis) means are currently under investigation, with multiple clinical trials ongoing. Macroscopic methods for removal involve both catheter- and endoscope-based therapies to remove the hematoma through minimally invasive surgery. Microscopic methods targeting hematoma clearance involve augmenting endogenous clearance pathways for red blood cells and altering the balance between phagocytosis and red blood cell lysis with the release of potentially harmful constituents (e.g. hemoglobin and iron) into the extracellular space. [ABSTRACT FROM AUTHOR]

Background: A previous study in our laboratory showed the neuroprotective effects of COA-Cl, a novel synthesized adenosine analog, in a rat cerebral ischemia model. The purpose of the present study was to evaluate the neuroprotective effects of COA-Cl in intracerebral hemorrhage (ICH), another common type of stroke, and investigate potential mechanisms of action.Methods: Adult Sprague-Dawley rats received an injection of 100 µl autologous whole blood into the right basal ganglia. COA-Cl (30 µg/kg) was injected intracerebroventricularly 10 minutes after ICH. A battery of motor deficit tests were performed at 1 day, 3 days, 5 days, and 7 days after ICH. To investigate the mechanism of action, brain water content, TUNEL staining and 8-OHdG immunostaining, and ELISA (to assess oxidative stress) were used.Results: COA-Cl treatment significantly attenuated sensorimotor deficits and reduced brain edema 1 day after ICH. Furthermore, the numbers of perihematomal TUNEL- and 8-OHdG-positive cells were significantly decreased in COA-Cl treated ICH rats.Conclusions: These results indicate that COA-Cl has neuroprotective effects in ICH. Furthermore, our study provides evidence that COA-Cl may reduce oxidative stress, which may be one mechanism underlying its neuroprotective effects. [ABSTRACT FROM AUTHOR]

Highlights: [•] Causes of bleeding. [•] Natural history of ICH. [•] ICH animal models. [•] Systemic responses after ICH. [•] Therapeutic targets and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

The current study examines nestin expression after intracerebral hemorrhage (ICH), the role of different blood components in nestin upregulation, and the possibility that low doses of thrombin that induce tolerance to brain injury (thrombin preconditioning) might also induce nestin expression. Adult male Sprague–Dawley rats received an intracaudate injection of either whole blood, thrombin (1 or 5 U) or red blood cells (RBCs). Animals were sacrificed for single and double labeling immunohistochemistry to identify which cells express nestin, and for Western blotting to quantify nestin expression. By immunohistochemistry, nestin immunoreactivity was present in large numbers of astrocytes, surrounding the hematoma from day 3 to 1 week after ICH. After 2 weeks, nestin immunoreactivity was co-localized with a neuronal marker (neuronal specific enolase). By Western blot analysis, nestin was strongly expressed at day 3 (P<0.01) and 1 week (P<0.01), and expression persisted for at least 1 month (P<0.05). Intracerebral injection of thrombin or lysed RBCs resulted in a marked increase in nestin expression. Interestingly, injection of a low dose of thrombin that induces brain tolerance also upregulated nestin. The ICH-induced nestin expression in astrocytes may reflect an early response of these cells to injury, while the delayed expression in neurons might be a part of the adaptative response to injury perhaps leading to recovery of function. Nestin induction by a low dose of thrombin suggests that specific receptor-mediated pathways are involved in inducing nestin expression and that nestin may play a role in thrombin preconditioning. [Copyright &y& Elsevier]

White matter (WM) injury and survival after intracerebral hemorrhage (ICH) has received insufficient attention. WM disruption surrounding the hematoma has been documented in animal models with histology, but rarely in human ICH with noninvasive means, like magnetic resonance imaging (MRI). A few human MRI studies have investigated changes in long WM tracts after ICH remote from the hematoma, like the corticospinal tract, but have not attempted to obtain an unbiased quantification of WM changes within and around the hematoma over time. This study attempts such quantification from 3 to 30 days post ictus. Thirteen patients with mild to moderate ICH underwent diffusion tensor imaging (DTI) MRI at 3, 14, and 30 days. Fractional anisotropy (FA) maps were used to calculate the volume of tissue with FA > 0.5, both within the hematoma (lesion) and in the perilesional tissue. At day 3, the percentages of both lesional and perilesional tissue with an FA > 0.5 were significantly less than contralateral, unaffected, anatomically identical tissue. This perilesional contralateral difference persisted at day 14, but there was no significant difference at day 30. The loss of perilesional tissue with FA > 0.5 increased with increasing hematoma size at day 3 and day 14. All patients had some tissue within the lesion with FA > 0.5 at all time points. This did not decrease with duration after ictus, suggesting the persistence of white matter within the hematoma/lesion. These results outline an approach to quantify WM injury, both within and surrounding the hematoma, after mild to moderate ICH using DTI MRI. This may be important for monitoring treatment strategies, such as hematoma evacuation, and assessing efficacy noninvasively. [ABSTRACT FROM AUTHOR]

Hemopexin (Hpx) is critical for hemin scavenging after the erythrocyte lysis that occurs following intracerebral hemorrhage (ICH). Low-density lipoprotein receptor-related protein-1 (LRP1, also called CD91) is an important receptor through which the hemin-Hpx complex can undergo endocytosis. This study investigated changes in the hemin-Hpx-CD91 axis in both hematoma and perihematomal tissue in a large animal ICH model. The effect of deferoxamine (DFX) on hemin-Hpx-CD91 was also examined. The study consisted of two parts. First, piglets had an injection of autologous blood into the right frontal lobe of brain and were euthanized from day 1 to day 7. Hematoma and perihematomal tissue of brains were used for hemin assay, immunohistochemistry, and immunofluorescence. Second, piglets with ICH were treated with deferoxamine or vehicle, and were euthanized for hemin measurement and Hpx and CD91 immunohistochemistry. We found that there was an increase of hemin levels within the hematoma and perihematomal brain tissue after ICH. Hpx and CD91-positive cells were present in the clot and perihematomal tissue from day 1. Hpx and CD91 positive cells were Iba1 positive. After DFX therapy, hemin dropped markedly in the hematoma and perihematomal brain tissue. Furthermore, DFX treatment decreased the number of Hpx and CD91 positive cells in and around the hematoma. In conclusion, hemin accumulation occurs in and around the hematoma. Increases in Hpx and CD91 may be important in scavenging that hemin. DFX treatment decreased hemin release from the hematoma and reduced the expression of Hpx and CD91. [ABSTRACT FROM AUTHOR]

Abstract Brain iron overload is involved in brain injury after intracerebral hemorrhage (ICH). There is evidence that systemic administration of minocycline reduces brain iron level and improves neurological outcome in experimental models of hemorrhagic and ischemic stroke. However, there is evidence in cerebral ischemia that minocycline is not protective in aged female animals. Since most ICH research has used male models, this study was designed to provide an overall view of ICH-induced iron deposits at different time points (1 to 28 days) in aged (18-month old) female Fischer 344 rat ICH model and to investigate the neuroprotective effects of minocycline in those rats. According to our previous studies, we used the following dosing regimen (20 mg/kg, i.p. at 2 and 12 h after ICH onset followed by 10 mg/kg, i.p., twice a day up to 7 days). T2-, T2⁎-weighted and T2⁎ array MRI was performed at 1, 3, 7 and 28 days to measure brain iron content, ventricle volume, lesion volume and brain swelling. Immunohistochemistry was used to examine changes in iron handling proteins, neuronal loss and microglial activation. Behavioral testing was used to assess neurological deficits. In aged female rats, ICH induced long-term perihematomal iron overload with upregulated iron handling proteins, neuroinflammation, brain atrophy, neuronal loss and neurological deficits. Minocycline significantly reduced ICH-induced perihematomal iron overload and iron handling proteins. It further reduced brain swelling, neuroinflammation, neuronal loss, delayed brain atrophy and neurological deficits. These effects may be linked to the role of minocycline as an iron chelator as well as an inhibitor of neuroinflammation. Highlights • ICH caused brain iron overload in aged female rats. • ICH resulted in reproducible brain swelling and brain atrophy in aged female rats. • Minocycline reduced ICH-induced brain iron overload and brain damage in aged female rats. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) is the most common hemorrhagic stroke subtype, and rates are increasing with an aging population. Despite an increase in research and trials of therapies for ICH, mortality remains high and no interventional therapy has been demonstrated to improve outcomes. We review known mechanisms of injury, recent clinical trial results, and newly discovered signaling pathways involved in hematoma clearance. Enthusiasm remains high for methods of minimally invasive clot removal as well as pharmacologic strategies to improve recovery after ICH, both of which are currently being evaluated in clinical trials. This article is part of the Special Issue entitled ‘Cerebral Ischemia’. [ABSTRACT FROM AUTHOR]