scholarly journals The neutrophil enzyme myeloperoxidase directly modulates neuronal response after subarachnoid hemorrhage, a sterile injury model

2019 ◽  
Author(s):  
Aminata P. Coulibaly ◽  
Pinar Pezuk ◽  
Paul Varghese ◽  
William Gartman ◽  
Danielle Triebwasser ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cognitive Deficits ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Neuronal Response ◽  
Neutrophil Infiltration ◽  
Cell Types ◽  
Brain Parenchyma ◽  
Cerebral Injury ◽  
Biologically Active ◽  
The Brain

AbstractNeutrophil infiltration into the central nervous system (CNS) after injury is associated with cognitive deficits. Using a murine model of aneurysmal subarachnoid hemorrhage (SAH), we elucidate the location and mode of action of neutrophils in the CNS. Following SAH, neutrophils infiltrate the meninges, and not the brain parenchyma. Mice lacking functional myeloperoxidase (MPO KO), a neutrophil enzyme, lack both the meningeal neutrophil infiltration and the cognitive deficits associated with delayed cerebral injury from SAH. The re-introduction of biologically active MPO, and its substrate hydrogen peroxide, to the cerebrospinal fluid of MPO KO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH. This implicates MPO as a mediator of neuronal dysfunction in SAH. Using primary neuronal and astrocyte cultures, we demonstrate that MPO directly affects the function of both cell types. Neurons exposed to MPO and its substrate show decreased calcium activity at baseline and after stimulation with potassium chloride. In addition, MPO and its substrate lead to significant astrocyte loss in culture, a result observed in the brain after SAH as well. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.

The neutrophil enzyme myeloperoxidase directly modulates neuronal response after subarachnoid hemorrhage, a sterile injury model

2020 ◽  
Author(s):  
Aminata P. Coulibaly ◽  
Pinar Pezuk ◽  
Paul Varghese ◽  
William Gartman ◽  
Danielle Triebwasser ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cognitive Deficits ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Neuronal Response ◽  
Neutrophil Infiltration ◽  
Brain Parenchyma ◽  
Biologically Active ◽  
Cns Injury ◽  
And Function ◽  
The Brain

Abstract Background: Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system (CNS) is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity, direct or indirect, influences CNS function in SAH. As such, the present project aims to elucidate neutrophil factors and mechanisms mediating CNS injury and cognitive deficits after SAH. Methods: Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. Also, in vitro techniques were used to elucidate whether neutrophils directly or indirectly affect neuronal function after SAH. Results: Our results show that following SAH, neutrophils infiltrate the meninges, and not the brain parenchyma. Mice lacking functional myeloperoxidase (MPO KO), a neutrophil enzyme, lack both the meningeal neutrophil infiltration and the cognitive deficits associated with SAH. The re-introduction of biologically active MPO, and its substrate hydrogen peroxide, to the cerebrospinal fluid of MPO KO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH. Furthermore, MPO directly affects the function of both primary neurons and astrocytes in culture. Neurons exposed to MPO and its substrate show decreased calcium activity at baseline and after stimulation with potassium chloride. In addition, MPO and its substrate lead to significant astrocyte loss in culture, phenocopying a result observed in the brain after SAH. Conclusions: These results implicate MPO as a mediator of neuronal dysfunction in SAH through direct effect on both neurons and astrocytes. Finally, these results show that, in SAH, the activity of innate immune cells in the meninges can modulate the activity and function of the underlying brain tissue.

The neutrophil enzyme myeloperoxidase modulates neuronal response after subarachnoid hemorrhage, a sterile injury model

2020 ◽  
Author(s):  
Aminata P. Coulibaly ◽  
Pinar Pezuk ◽  
Paul Varghese ◽  
William Gartman ◽  
Danielle Triebwasser ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cognitive Deficits ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Neuronal Response ◽  
Neutrophil Infiltration ◽  
Brain Parenchyma ◽  
Biologically Active ◽  
Cns Injury ◽  
The Brain

Abstract Background: Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system (CNS) is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences CNS function in SAH. As such, the present project aims to elucidate neutrophil factors and mechanisms mediating CNS injury and cognitive deficits after SAH. Methods: Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. Also, in vitro techniques were used to elucidate how neutrophils affect cellular function of neurons and glia after SAH. Results: Our results show that following SAH, neutrophils infiltrate the meninges, and not the brain parenchyma. Mice lacking functional myeloperoxidase (MPO KO), a neutrophil enzyme, lack both the meningeal neutrophil infiltration and the cognitive deficits associated with SAH. The re-introduction of biologically active MPO, and its substrate hydrogen peroxide, to the cerebrospinal fluid of MPO KO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH. Furthermore, in culture, MPO affects the function of both primary neurons and astrocytes, though not microglia. Neurons exposed to MPO and its substrate show decreased calcium activity at baseline and after stimulation with potassium chloride. In addition, MPO and its substrate lead to significant astrocyte loss in culture, phenocopying a result observed in the brain after SAH. Conclusions: These results implicate MPO as a mediator of neuronal dysfunction in SAH through their effect on both neurons and astrocytes. Finally, these results show that, in SAH, the activity of innate immune cells in the meninges can modulate the activity and function of the underlying brain tissue.

Neutrophil Enzyme Myeloperoxidase Modulates Neuronal Response in a Model of Subarachnoid Hemorrhage by Venous Injury

Stroke ◽  
2021 ◽  
Vol 52 (10) ◽  
pp. 3374-3384
Author(s):  
Aminata P. Coulibaly ◽  
Pinar Pezuk ◽  
Paul Varghese ◽  
William Gartman ◽  
Danielle Triebwasser ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Subarachnoid Hemorrhage ◽  
Cognitive Deficits ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Neuronal Response ◽  
Neutrophil Infiltration ◽  
Biologically Active ◽  
Venous Injury

Background and Purpose: Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences central nervous system function in SAH. The present project aims to elucidate which neutrophil factors mediate central nervous system injury and cognitive deficits after SAH. Methods: Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. In vivo and in vitro techniques were used to investigate possible pathways of neutrophils effect after SAH. Results: Our results show that mice lacking functional MPO (myeloperoxidase), a neutrophil enzyme, lack both the meningeal neutrophil infiltration (wild type, sham 872 cells/meninges versus SAH 3047, P =0.023; myeloperoxidase knockout [MPOKO], sham 1677 versus SAH 1636, P =NS) and erase the cognitive deficits on Barnes maze associated with SAH (MPOKO sham versus SAH, P =NS). The reintroduction of biologically active MPO, and its substrate hydrogen peroxide (H 2 O 2 ), to the cerebrospinal fluid of MPOKO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH (time to goal box MPOKO sham versus MPOKO+MPO/H 2 O 2 , P =0.001). We find evidence of changes in neurons, astrocytes, and microglia with MPO/H 2 O 2 suggesting the effect of MPO may have complex interactions with many cell types. Neurons exposed to MPO/H 2 O 2 show decreased calcium activity at baseline and after stimulation with potassium chloride. Although astrocytes and microglia are affected, changes seen in astrocytes are most consistent with inflammatory changes that likely affect neurons. Conclusions: These results implicate MPO as a mediator of neuronal dysfunction in SAH through its effect on both neurons and glia. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.

scholarly journals Elevated Baseline C-Reactive Protein as a Predictor of Outcome After Aneurysmal Subarachnoid Hemorrhage

Neurosurgery ◽  
2015 ◽  
Vol 77 (5) ◽  
pp. 786-793 ◽  
Author(s):  
◽  
Carole L. Turner ◽  
Karol Budohoski ◽  
Christopher Smith ◽  
Peter J. Hutchinson ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
White Blood Cells ◽  
Cerebral Injury ◽  
World Federation ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Poor Outcome ◽  
Fisher Grade ◽  
Good Grade

Abstract BACKGROUND: There remains a proportion of patients with unfavorable outcomes after aneurysmal subarachnoid hemorrhage, of particular relevance in those who present with a good clinical grade. A forewarning of those at risk provides an opportunity towards more intensive monitoring, investigation, and prophylactic treatment prior to the clinical manifestation of advancing cerebral injury. OBJECTIVE: To assess whether biochemical markers sampled in the first days after the initial hemorrhage can predict poor outcome. METHODS: All patients recruited to the multicenter Simvastatin in Aneurysmal Hemorrhage Trial (STASH) were included. Baseline biochemical profiles were taken between time of ictus and day 4 post ictus. The t-test compared outcomes, and a backwards stepwise binary logistic regression was used to determine the factors providing independent prediction of an unfavorable outcome. RESULTS: Baseline biochemical data were obtained in approximately 91% of cases from 803 patients. On admission, 73% of patients were good grade (World Federation of Neurological Surgeons grades 1 or 2); however, 84% had a Fisher grade 3 or 4 on computed tomographic scan. For patients presenting with good grade on admission, higher levels of C-reactive protein, glucose, and white blood cells and lower levels of hematocrit, albumin, and hemoglobin were associated with poor outcome at discharge. C-reactive protein was found to be an independent predictor of outcome for patients presenting in good grade. CONCLUSION: Early recording of C-reactive protein may prove useful in detecting those good grade patients who are at greater risk of clinical deterioration and poor outcome.

scholarly journals Neuronal apoptosis: signal and cell diversity

1969 ◽  
Vol 40 (1) ◽  
pp. 124-133
Author(s):  
Lina Vanessa Becerra ◽  
Hernán José Pimienta
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Neuronal Response ◽  
Neuronal Cell ◽  
Cell Types ◽  
Point Of View ◽  
Trophic Factors ◽  
Cell Diversity ◽  
Apoptotic Pathways ◽  
The Brain

Programmed cell death occurs as a physiological process during development. In the brain and spinal cord this event determines the number and location of the different cell types. In adulthood, programmed cell death or apoptosis is more restricted but it may play a major role in different acute and chronic pathological entities. However, in contrast to other tissues where apoptosis has been widely documented from a morphological point of view, in the central nervous system complete anatomical evidence of apoptosis is scanty. In spite of this there is consensus about the activation of different signal systems associated to programmed cell death. In the present article we attempt to summarize the main apoptotic pathways so far identified in nervous tissue. Considering that apoptotic pathways are multiple, the neuronal cell types are highly diverse and specialized and that neuronal response to injury and survival depends upon tissue context, (i.e., preservation of connectivity, glial integrity and cell matrix, blood supply and trophic factors availability) what is relevant for the apoptotic process in a sector of the brain may not be important in another.

scholarly journals Hypoxic-Ischaemic Encephalopathy and the Blood-Brain Barrier in Neonates

2017 ◽  
Vol 39 (1-4) ◽  
pp. 49-58 ◽  
Author(s):  
Wei Ling Amelia Lee ◽  
Adina T. Michael-Titus ◽  
Divyen K. Shah
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Cerebral Injury ◽  
Brain Barrier ◽  
Transport Systems ◽  
Permeability Barrier ◽  
Cell Based Therapy ◽  
Blood Brain ◽  
The Brain

This review aims to highlight a possible relationship between hypoxic-ischaemic encephalopathy (HIE) and the disruption of the blood-brain barrier (BBB). Inflammatory reactions perpetuate a large proportion of cerebral injury. The extent of injury noted in HIE is not only determined by the biochemical cascades that trigger the apoptosis-necrosis continuum of cell death in the brain parenchyma, but also by the breaching of the BBB by pro-inflammatory factors. We examine the changes that contribute to the breakdown of the BBB that occur during HIE at a macroscopic, cellular, and molecular level. The BBB is a permeability barrier which separates a large majority of brain areas from the systemic circulation. The concept of a physiological BBB is based at the anatomical level on the neurovascular unit (NVU). The NVU consists of various cellular components that jointly regulate the exchanges that occur at the interface between the systemic circulation and the brain parenchyma. There is increased understanding of the contribution of the components of the NVU, e.g., astrocytes and pericytes, to the maintenance of this physiological barrier. We also explore the development of therapeutic options in HIE, such as harnessing the transport systems in the BBB, to enable the delivery of large molecules with molecular Trojan horse technology, and the reinforcement of the physical barrier with cell-based therapy which utilizes endothelial progenitor cells and stem cells.

scholarly journals Subependymal Zone: Immunohistochemically Distinct Compartment in the Adult Mammalian Forebrain

2004 ◽  
Vol 47 (4) ◽  
pp. 235-242 ◽  
Author(s):  
Jaroslav Mokrý ◽  
Dana Čížková ◽  
Jan Österreicher
Keyword(s):  
Cell Types ◽  
Brain Parenchyma ◽  
Mammalian Brain ◽  
Histological Structure ◽  
Astroglial Cell ◽  
Neuronal Markers ◽  
Subependymal Zone ◽  
Rat Forebrain ◽  
The Brain ◽  
Migratory Stream

The subependymal zone (SEZ) lining lateral walls of the lateral cerebral ventricles represents the site of active neurogenesis in the brain of adult mammals. Peroxidase immunohistochemistry performed in paraffin-embedded sections reveals that structural organization of the SEZ differs from other regions in the brain. The SEZ is devoid of synapses that are abundant in the adjacent striatal neuropil. Therefore immunostaining of synaptophysin detects sharp borders of the SEZ. Using immunophenotypization, we identified cell types constituting the SEZ in the intact rat forebrain. The presence of neural progenitor/stem cells was confirmed by finding of nestin-immunopositive cells. Detection of the astroglial marker GFAP confirmed that astrocytes represented major supporting elements responsible for creating a unique microenvironment of the SEZ. One type of the astroglia participated in covering surfaces of the blood vessels and boundaries of the SEZ. The second astroglial cell type formed branched elongated tubes that enwrapped other SEZ cell types with their cytoplasmic extensions. The interior of astrocytic channels was occupied with small densely aggregated NCAM-immunoreactive neuroblasts. Bipolar morphology indicated that these cells probably underwent migration. Immunodetection of other neuronal markers like β-III tubulin, MAP-2 and Pan neurofilaments identified positive cells in the neighbouring brain parenchyma but not in the SEZ. The rostral migratory stream (RMS) linked with the anterior SEZ had a similar structural arrangement. It contained a large amount of nestin+and vimentin+cells. The RMS consisted of GFAP+astrocytic tubes ensheathing NCAM+neuroblasts. On the contrary to the SEZ, the RMS neuroblasts expressed β-III tubulin. However, markers of postmitotic neurons MAP-2, Pan neurofilaments and synaptophysin were not expressed in the RMS. Our study describes a complex histological structure of the rat SEZ, identifies its individual cell types and demonstrates a usefulness of immunohistochemical detection of cell-specific markers in a study of microenvironment forming neurogenic zones in the mammalian brain.

scholarly journals Immovable Object Meets Unstoppable Force? Dialogue Between Resident and Peripheral Myeloid Cells in the Inflamed Brain

2020 ◽  
Vol 11 ◽  
Author(s):  
Alanna G. Spiteri ◽  
Claire L. Wishart ◽  
Nicholas J. C. King
Keyword(s):  
Myeloid Cells ◽  
Cell Types ◽  
Brain Parenchyma ◽  
Specific Cell ◽  
Novel Treatments ◽  
Experimental Systems ◽  
Immune Mediated ◽  
Recent Developments ◽  
The Central Nervous System ◽  
The Brain

Inflammation of the brain parenchyma is characteristic of neurodegenerative, autoimmune, and neuroinflammatory diseases. During this process, microglia, which populate the embryonic brain and become a permanent sentinel myeloid population, are inexorably joined by peripherally derived monocytes, recruited by the central nervous system. These cells can quickly adopt a morphology and immunophenotype similar to microglia. Both microglia and monocytes have been implicated in inducing, enhancing, and/or maintaining immune-mediated pathology and thus disease progression in a number of neuropathologies. For many years, experimental and analytical systems have failed to differentiate resident microglia from peripherally derived myeloid cells accurately. This has impeded our understanding of their precise functions in, and contributions to, these diseases, and hampered the development of novel treatments that could target specific cell subsets. Over the past decade, microglia have been investigated more intensively in the context of neuroimmunological research, fostering the development of more precise experimental systems. In light of our rapidly growing understanding of these cells, we discuss the differential origins of microglia and peripherally derived myeloid cells in the inflamed brain, with an analysis of the problems resolving these cell types phenotypically and morphologically, and highlight recent developments enabling more precise identification.

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