Clearance of Neutrophils From ICH-Affected Brain by Macrophages Is Beneficial and Is Assisted by Lactoferrin and CD91.

Background: Within hours after intracerebral hemorrhage (ICH) onset, masses of polymorphonuclear neutrophils (PMNs) infiltrate the ICH-affected brain. After degranulation involving controlled release of many toxic antimicrobial molecules, the PMNs undergo rapid apoptosis and then are removed by phagocytic microglia/macrophages (MΦ) through a process called efferocytosis. Effective removal of PMNs may limit secondary brain damage and inflammation; however, the molecular mechanisms governing these cleanup activities are not well understood.

Contribution of TRPC Channels in Neuronal Excitotoxicity Associated With Neurodegenerative Disease and Ischemic Stroke.

The seven canonical members of transient receptor potential (TRPC) proteins form cation channels that evoke membrane depolarization and intracellular calcium concentration ([Ca] ) rise, which are not only important for regulating cell function but their deregulation can also lead to cell damage. Recent studies have implicated complex roles of TRPC channels in neurodegenerative diseases including ischemic stroke. Brain ischemia reduces oxygen and glucose supply to neurons, i.

Optimized lactoferrin as a highly promising treatment for intracerebral hemorrhage: Pre-clinical experience.

Intracerebral hemorrhage (ICH) is the deadliest form of stroke for which there is no effective treatment, despite an endless number of pre-clinical studies and clinical trials. The obvious therapeutic target is the neutralization of toxic products of red blood cell (RBC) lysis that lead to cytotoxicity, inflammation, and oxidative damage. We used rigorous approaches and translationally relevant experimental ICH models to show that lactoferrin-(LTF)-based monotherapy is uniquely robust in reducing brain damage after ICH.

The Mitochondria-Derived Peptide Humanin Improves Recovery from Intracerebral Hemorrhage: Implication of Mitochondria Transfer and Microglia Phenotype Change.

Astrocytes are an integral component of the neurovascular unit where they act as homeostatic regulators, especially after brain injuries, such as stroke. One process by which astrocytes modulate homeostasis is the release of functional mitochondria (Mt) that are taken up by other cells to improve their function. However, the mechanisms underlying the beneficial effect of Mt transfer are unclear and likely multifactorial.

Brain Cleanup as a Potential Target for Poststroke Recovery: The Role of RXR (Retinoic X Receptor) in Phagocytes.

Background and Purpose- Phagocytic cells, such as microglia and blood-derived macrophages, are a key biological modality responsible for phagocytosis-mediated clearance of damaged, dead, or displaced cells that are compromised during senescence or pathological processes, including after stroke. This process of clearance is essential to eliminate the source of inflammation and to allow for optimal brain repair and functional recovery. Transcription factor, RXR (retinoic-X-receptor) is strongly implicated in phagocytic functions regulation, and as such could represent a novel target for brain recovery after stroke.

Serial Metabolic Evaluation of Perihematomal Tissues in the Intracerebral Hemorrhage Pig Model.

Purpose: Perihematomal edema (PHE) occurs in patients with intracerebral hemorrhage (ICH) and is often used as surrogate of secondary brain injury. PHE resolves over time, but little is known about the functional integrity of the tissues that recover from edema. In a pig ICH model, we aimed to assess metabolic integrity of perihematoma tissues by using non-invasive magnetic resonance spectroscopy (MRS).

Excitatory pathway engaging glutamate, calcineurin, and NFAT upregulates IL-4 in ischemic neurons to polarize microglia.

Excitotoxicity and microglia/macrophage over-activation are the important pathogenic steps in brain damage caused by ischemic stroke. Recent studies from our group suggest that the neurons in ischemic penumbra generate an anti-inflammatory cytokine, interleukin-4 (IL-4). This neuron-produced IL-4 could subsequently convert surrounding microglia/macrophages to a reparative (M2)-phenotype.

Beneficial Role of Neutrophils Through Function of Lactoferrin After Intracerebral Hemorrhage.

Background And Purpose: Intracerebral hemorrhage (ICH) is a devastating disease with a 30-day mortality of ~50%. There are no effective therapies for ICH. ICH results in brain damage in 2 major ways: through the mechanical forces of extravasated blood and then through toxicity of the intraparenchymal blood components including hemoglobin/iron.

Serial quantitative neuroimaging of iron in the intracerebral hemorrhage pig model.

Iron released after intracerebral hemorrhage (ICH) is damaging to the brain. Measurement of the content and distribution of iron in the hematoma could predict brain damage. In this study, 16 Yorkshire piglets were subjected to autologous blood injection ICH model and studied longitudinally using quantitative susceptibility mapping and R2* relaxivity MRI on day 1 and 7 post-ICH.

Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage.

Shortly after intracerebral hemorrhage, neutrophils infiltrate the intracerebral hemorrhage-injured brain. Once within the brain, neutrophils degranulate, releasing destructive molecules that may exacerbate brain damage. However, neutrophils also release beneficial molecules, including iron-scavenging lactoferrin that may limit hematoma/iron-mediated brain injury after intracerebral hemorrhage.

Phagocytosis Assay of Microglia for Dead Neurons in Primary Rat Brain Cell Cultures.

Clearance of dead brain tissue including the dead neurons through phagocytosis is an endogenous function of microglia in the brain, which is critical for inflammation resolution after ischemic stroke or head trauma. By regulating the function or polarization status of microglia, we may control their phagocytosis efficacy and therefore the cleanup process for the dead brain tissue. We cultured rat cortical neurons and microglia from the same litter of embryos.

Dimethyl Fumarate Protects Brain From Damage Produced by Intracerebral Hemorrhage by Mechanism Involving Nrf2.

Background And Purpose: Intracerebral hemorrhage (ICH) represents a devastating form of stroke for which there is no effective treatment. This preclinical study was designed to evaluate dimethyl fumarate (DMF), a substance recently approved for the treatment of multiple sclerosis, as therapy for ICH. We hypothesized that DMF through activating the master regulator of cellular self-defense responses, transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), would act as effective treatment for ICH-mediated damage.

Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance.

As a consequence of intracerebral hemorrhage (ICH), blood components enter brain parenchyma causing progressive damage to the surrounding brain. Unless hematoma is cleared, the reservoirs of blood continue to inflict injury to neurovascular structures and blunt the brain repair processes. Microglia/macrophages (MMΦ) represent the primary phagocytic system that mediates the cleanup of hematoma.

Polymorphonuclear neutrophil in brain parenchyma after experimental intracerebral hemorrhage.

Polymorphonuclear neutrophils (PMNs) infiltration into brain parenchyma after cerebrovascular accidents is viewed as a key component of secondary brain injury. Interestingly, a recent study of ischemic stroke suggests that after ischemic stroke, PMNs do not enter brain parenchyma and as such may cause no harm to the brain. Thus, the present study was designed to determine PMNs' behavior after intracerebral hemorrhage (ICH).