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.

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.

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.

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 Vascular Dysfunction Induced by Mercury Exposure

2019 ◽  
Vol 20 (10) ◽  
pp. 2435 ◽  
Author(s):  
Tetsuya Takahashi ◽  
Takayoshi Shimohata
Keyword(s):  
Oxidative Stress ◽  
Vascular Dysfunction ◽  
Brain Parenchyma ◽  
Transport Systems ◽  
Mehg Exposure ◽  
In Vivo Models ◽  
The Central Nervous System ◽  
The Brain

Methylmercury (MeHg) causes severe damage to the central nervous system, and there is increasing evidence of the association between MeHg exposure and vascular dysfunction, hemorrhage, and edema in the brain, but not in other organs of patients with acute MeHg intoxication. These observations suggest that MeHg possibly causes blood–brain barrier (BBB) damage. MeHg penetrates the BBB into the brain parenchyma via active transport systems, mainly the l-type amino acid transporter 1, on endothelial cell membranes. Recently, exposure to mercury has significantly increased. Numerous reports suggest that long-term low-level MeHg exposure can impair endothelial function and increase the risks of cardiovascular disease. The most widely reported mechanism of MeHg toxicity is oxidative stress and related pathways, such as neuroinflammation. BBB dysfunction has been suggested by both in vitro and in vivo models of MeHg intoxication. Therapy targeted at both maintaining the BBB and suppressing oxidative stress may represent a promising therapeutic strategy for MeHg intoxication. This paper reviews studies on the relationship between MeHg exposure and vascular dysfunction, with a special emphasis on the BBB.

scholarly journals In vitro models of the blood–brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use

2016 ◽  
Vol 36 (5) ◽  
pp. 862-890 ◽  
Author(s):  
Hans C Helms ◽  
N Joan Abbott ◽  
Malgorzata Burek ◽  
Romeo Cecchelli ◽  
Pierre-Olivier Couraud ◽  
...  
Keyword(s):  
Cell Culture ◽  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
Culture Models ◽  
Cell Culture Models ◽  
The Brain

The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic components of plasma and xenobiotics. This “blood-brain barrier” function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug transport to the brain and studies of endothelial cell biology and pathophysiology. In this review, we aim to give an overview of established in vitro blood–brain barrier models with a focus on their validation regarding a set of well-established blood–brain barrier characteristics. As an ideal cell culture model of the blood–brain barrier is yet to be developed, we also aim to give an overview of the advantages and drawbacks of the different models described.

scholarly journals Properties of a New Food Supplement Containing Actinia equina Extract

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 945
Author(s):  
Marika Lanza ◽  
Giovanna Casili ◽  
Giovanna Loredana La Torre ◽  
Daniele Giuffrida ◽  
Archimede Rotondo ◽  
...  
Keyword(s):  
In Vitro Study ◽  
Neutrophil Infiltration ◽  
Food Supplement ◽  
Biologically Active ◽  
In Vivo Model ◽  
Related Factor ◽  
Nuclear Factor ◽  
Anti Inflammatory

Marine species represent a great source of biologically active substances; Actinia equina (AE), an Anthozoa Cnidaria belonging to the Actinidiae family, have been proposed as original food and have already been included in several cooking recipes in local Mediterranean shores, and endowed with excellent nutraceutical potential. The aim of this study was to investigate some unexplored features of AE, through analytical screening and an in-vitro and in-vivo model. An in-vitro study, made on RAW 264.7 stimulated with H2O2, showed that the pre-treatment with AE exerted an antioxidant action, reducing lipid peroxidation and up-regulating antioxidant enzymes. On the other hand, the in-vivo study over murine model demonstrated that the administration of AE extracts is able to reduce the carrageenan (CAR)-induced paw edema. Furthermore, the histological damage due to the neutrophil infiltration is prevented, and this highlights precious anti-inflammatory features of the interesting food-stuff. Moreover, it was assessed that AE extract modulated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and The nuclear factor erythroid 2–related factor 2 (Nrf-2) pathways. In conclusion, our data demonstrated that thanks to the antioxidant and anti-inflammatory properties, AE extract could be used as a new food supplement for inflammatory pathology prevention.

scholarly journals A proline insertion-deletion in the spike glycoprotein fusion peptide of mouse hepatitis virus strongly alters neuropathology

2019 ◽  
Vol 294 (20) ◽  
pp. 8064-8087 ◽  
Author(s):  
Manmeet Singh ◽  
Abhinoy Kishore ◽  
Dibyajyoti Maity ◽  
Punnepalli Sunanda ◽  
Bankala Krishnarjuna ◽  
...  
Keyword(s):  
Hepatitis Virus ◽  
Mouse Hepatitis Virus ◽  
Brain Parenchyma ◽  
Fusion Peptides ◽  
Spike Glycoprotein ◽  
Fusion Event ◽  
Viral Spread ◽  
Secondary Amino ◽  
The Brain

Fusion peptides (FPs) in spike proteins are key players mediating early events in cell-to-cell fusion, vital for intercellular viral spread. A proline residue located at the central FP region has often been suggested to have a distinctive role in this fusion event. The spike glycoprotein from strain RSA59 (PP) of mouse hepatitis virus (MHV) contains two central, consecutive prolines in the FP. Here, we report that deletion of one of these proline residues, resulting in RSA59 (P), significantly affected neural cell syncytia formation and viral titers postinfection in vitro. Transcranial inoculation of C57Bl/6 mice with RSA59 (PP) or RSA59 (P) yielded similar degrees of necrotizing hepatitis and meningitis, but only RSA59 (PP) produced widespread encephalitis that extended deeply into the brain parenchyma. By day 6 postinfection, both virus variants were mostly cleared from the brain. Interestingly, inoculation with the RSA59 (P)–carrying MHV significantly reduced demyelination at the chronic stage. We also found that the presence of two consecutive prolines in FP promotes a more ordered, compact, and rigid structure in the spike protein. These effects on FP structure were due to proline's unique stereochemical properties intrinsic to its secondary amino acid structure, revealed by molecular dynamics and NMR experiments. We therefore propose that the differences in the severity of encephalitis and demyelination between RSA59 (PP) and RSA59 (P) arise from the presence or absence, respectively, of the two consecutive prolines in FP. Our studies define a structural determinant of MHV entry in the brain parenchyma important for altered neuropathogenesis.

RELATIONSHIP OF THE MET ALLELE OF THE BRAIN-DERIVED NEUROTROPHIC FACTOR VAL66MET POLYMORPHISM TO MEMORY AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE

Neurosurgery ◽  
2008 ◽  
Vol 63 (2) ◽  
pp. 198-203 ◽  
Author(s):  
Juhani Vilkki ◽  
Jaakko Lappalainen ◽  
Seppo Juvela ◽  
Katarzyna Kanarek ◽  
Juha A. Hernesniemi ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Neurotrophic Factor ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Brain Derived Neurotrophic Factor ◽  
Val66met Polymorphism ◽  
Relationship Of ◽  
The Brain

scholarly journals The CCL2-CCR2 astrocyte-cancer cell axis in tumor extravasation at the brain

2021 ◽  
Vol 7 (26) ◽  
pp. eabg8139
Author(s):  
Cynthia Hajal ◽  
Yoojin Shin ◽  
Leanne Li ◽  
Jean Carlos Serrano ◽  
Tyler Jacks ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Three Dimensional ◽  
Brain Parenchyma ◽  
Cell Axis ◽  
Chemokine Ligand ◽  
Chemokine Ligand 2 ◽  
The Brain

Although brain metastases are common in cancer patients, little is known about the mechanisms of cancer extravasation across the blood-brain barrier (BBB), a key step in the metastatic cascade that regulates the entry of cancer cells into the brain parenchyma. Here, we show, in a three-dimensional in vitro BBB microvascular model, that astrocytes promote cancer cell transmigration via their secretion of C-C motif chemokine ligand 2 (CCL2). We found that this chemokine, produced primarily by astrocytes, promoted the chemotaxis and chemokinesis of cancer cells via their C-C chemokine receptor type 2 (CCR2), with no notable changes in vascular permeability. These findings were validated in vivo, where CCR2-deficient cancer cells exhibited significantly reduced rates of arrest and transmigration in mouse brain capillaries. Our results reveal that the CCL2-CCR2 astrocyte-cancer cell axis plays a fundamental role in extravasation and, consequently, metastasis to the brain.

Sign in / Sign up

Export Citation Format

Share Document