scholarly journals Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin dependent mechanism

2018 ◽  
Author(s):  
Amanda G. Chung ◽  
Jennifer B. Frye ◽  
Jacob C. Zbesko ◽  
Eleni Constantopoulos ◽  
Megan Hayes ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Brain Ischemia ◽  
Molecular Profile ◽  
Central Component ◽  
Phagocytic Cells ◽  
Cholesterol Crystals ◽  
Neuronal Nuclei ◽  
Myelin Debris ◽  
Liquefactive Necrosis ◽  
The Brain

AbstractHere we used mouse models of heart and brain ischemia to compare the inflammatory response to ischemia in the heart, a protein rich organ, to the inflammatory response to ischemia in the brain, a lipid rich organ. We report that ischemia-induced inflammation resolves between 1 and 4 weeks in the heart compared to between 8 and 24 weeks in the brain. Importantly, we discovered that a second burst of inflammation occurs in the brain between 4 and 8 weeks following ischemia, which coincided with the appearance of cholesterol crystals within the infarct. This second wave shares a similar cellular and molecular profile with atherosclerosis and is characterized by high levels of osteopontin (OPN) and matrix metalloproteinases (MMPs). In order to test the role of OPN in areas of liquefactive necrosis, OPN-/- mice were subjected to brain ischemia. We found that at 7 weeks following stroke, the expression of pro-inflammatory proteins and MMPs was profoundly reduced in the infarct of the OPN-/- mice, although the number of cholesterol crystals was increased. OPN-/- mice exhibited faster recovery of motor function and a higher number of neuronal nuclei (NeuN) positive cells in the peri-infarct area at 7 weeks following stroke. Based on these findings we propose that the brain liquefies after stroke because phagocytic cells in the infarct are unable to efficiently clear cholesterol rich myelin debris, and that this leads to the perpetuation of an OPN-dependent inflammatory response characterized by high levels of degradative enzymes.Significance StatementThe inflammatory response to ischemia in the brain is different to the response to ischemic injury in other organs. In the brain, and for unknown reasons, dead tissue liquefies in response to ischemia by the process of liquefactive necrosis. However, the data we present here demonstrate that there is overlap between the pathophysiology of liquefactive necrosis and atherosclerosis. Specifically, we show that chronic stroke infarcts contain foamy macrophages, cholesterol crystals, high levels of OPN and MMPs, and a similar cytokine profile to atherosclerosis. Therefore, because cholesterol is a central component of myelin, liquefactive necrosis in response to stroke may be caused by an inflammatory response to cholesterol-rich myelin debris that is driven in large part by OPN and MMPs.

scholarly journals Gut Microbiome Influences The Neuroinflammatory Response To Traumatic Brain Injury

2021 ◽  
Author(s):  
Akshita Jade Kumar ◽  
Supinder Singh Bedi ◽  
Naama Toledano-Furman ◽  
Louis Carrillo ◽  
Fanni Cardenas ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Gut Microbiome ◽  
Central Component ◽  
Post Injury ◽  
Probiotic Treatment ◽  
Anti Inflammatory ◽  
Microglial Response ◽  
The Brain

Abstract Background: Traumatic brain injury (TBI) is a systemic injury that disrupts a complex arrangement of interacting cells in the brain and in the gastrointestinal tract (GI). Disruption in the brain results in neuroinflammation, in which microglia are a central component along with cytokines and other soluble factors [pro and anti-inflammatory microglia (M1:M2)]. Disruption in the GI due to TBI results in a systemic inflammation which is dependent upon the gut microbiome (GM). Gut microbiome can influence microglia in the brain via the gut-brain axis. In order to determine if the microbiome-microglia connections via the gut-brain axis can be modulated, we used probiotics and antibiotics in a rodent TBI model to evaluate the microbiome-microglial connections in acute and chronic experiments.Methods: The temporal effects of treatment (probiotics or antibiotics) were used to evaluate the gut-associated lymphoid tissue (GALT) influence on the microglial response at 72 hours or 21 days after a cortical contusion injury (CCI), a rodent model of TBI. Injured animals received daily probiotics, antibiotics, or no treatment. Sham-injured animals (controls) did not receive any treatment.Results: Twenty-one days of probiotic treatment attenuated the pro-inflammatory response of microglia (M1:M2) after CCI. The post-injury inflammatory response was heightened in the GALT with antibiotic-induced dysbiosis which resulted in amplification of the pro-inflammatory microglial response. Conclusions: Probiotic treatment after TBI is a potential therapeutic in attenuating microglial activation through anti-inflammatory signaling.

scholarly journals Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 994
Author(s):  
Natasha Ting Lee ◽  
Lin Kooi Ong ◽  
Prajwal Gyawali ◽  
Che Mohd Nasril Che Mohd Nassir ◽  
Muzaimi Mustapha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Inflammatory Response ◽  
Small Vessel Disease ◽  
Ischemia Reperfusion ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Purinergic Signalling ◽  
Vessel Disease ◽  
The Brain

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood–brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.

Integrative view of serpins in health and disease: the contribution of serpinA3

2020 ◽  
Author(s):  
Andrea Sanchez-Navarro ◽  
Isaac González-Soria ◽  
Rebecca Caldiño-Bohn ◽  
Norma A. Bobadilla
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Cellular Processes ◽  
Hormone Transport ◽  
Integrative View ◽  
Health And Disease ◽  
The Brain ◽  
Regulation Of Blood Pressure ◽  
Common Function

Serpins are a superfamily of proteins characterized by their common function as serine protease inhibitors. So far, 36 serpins from nine clades have been identified. These proteins are expressed in all the organs and are involved in multiple important functions such as the regulation of blood pressure, hormone transport, insulin sensitivity, and the inflammatory response. Diseases such as obesity, diabetes, cardiovascular, and kidney disorders are intensively studied to find effective therapeutic targets. Given serpins' outstanding functionality, the deficiency or overexpression of certain types of serpin have been associated with diverse pathophysiological events. In particular, we will focus on reviewing the studies evaluating the participation of serpins, and particularly SerpinA3, in diverse diseases that occur in relevant organs such as the brain, retinas, corneas, lungs, cardiac vasculature, and kidneys. In this review, we summarize the role of serpins in physiological and pathophysiological processes, as well as recent evidence on the crucial role of SerpinA3 in several pathologies. Finally, we emphasize the importance of SerpinA3 in regulating cellular processes such as angiogenesis, apoptosis, fibrosis, oxidative stress, and the inflammatory response.

scholarly journals The Immunopathogenesis of Neuroinvasive Lesions of SARS-CoV-2 Infection in COVID-19 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Shamila D. Alipoor ◽  
Esmaeil Mortaz ◽  
Mohammad Varahram ◽  
Johan Garssen ◽  
Ian M. Adcock
Keyword(s):  
Transport Mechanism ◽  
Respiratory Rhythm ◽  
Olfactory Nerve ◽  
Severe Respiratory Distress ◽  
Neuronal Nuclei ◽  
The World ◽  
Neurological Effects ◽  
The Brain ◽  
Trigger Cell Death

The new coronavirus disease COVID-19 was identified in December 2019. It subsequently spread across the world with over 125 M reported cases and 2.75 M deaths in 190 countries. COVID-19 causes severe respiratory distress; however, recent studies have reported neurological consequences of infection by the COVID-19 virus SARS-CoV-2 even in subjects with mild infection and no initial neurological effects. It is likely that the virus uses the olfactory nerve to reach the CNS and that this transport mechanism enables virus access to areas of the brain stem that regulates respiratory rhythm and may even trigger cell death by alteration of these neuronal nuclei. In addition, the long-term neuronal effects of COVID-19 suggest a role for SARS-CoV-2 in the development or progression of neurodegerative disease as a result of inflammation and/or hypercoagulation. In this review recent findings on the mechanism(s) by which SARS-CoV-2 accesses the CNS and induces neurological dysregulation are summarized.

Keep Your Brain Tissue Healthy

2021 ◽  
pp. 27-66
Author(s):  
Charles Alessi ◽  
Larry W. Chambers ◽  
Muir Gray
Keyword(s):  
Physical Activity ◽  
Immune System ◽  
Inflammatory Response ◽  
Stress Reduction ◽  
Indirect Effects ◽  
Cognitive Abilities ◽  
Direct And Indirect Effects ◽  
The Impact ◽  
The Brain

This chapter starts by advising how to reduce the impact of stress. When stress becomes long term, the immune system becomes less sensitive to cortisol, and since inflammation is partly regulated by this hormone, this decreased sensitivity heightens the inflammatory response and allows inflammation to get out of control, increasing our risk of many diseases. You can reduce your stress yourself through a variety of methods, including physical activity and mindfulness-based stress reduction. Adequate sleep is also a major factor that can improve cognitive abilities and reduce the risk of dementia, and this chapter outlines what we need to know about sleep cycles, insomnia, and sleep disordered breathing, and how to sleep more and sleep better. The chapter then covers how to protect your brain from over medication (polypharmacy). It finishes by discussing how to maintain and indeed increase your levels of physical activity, and how increasing physical activity has both direct and indirect effects on the brain.

Songs to Syntax

2011 ◽  
Vol 5 (4) ◽  
pp. 22-32 ◽  
Author(s):  
Robert C. Berwick
Keyword(s):  
Auditory Perception ◽  
Convergent Evolution ◽  
Vocal Learning ◽  
Brain Regions ◽  
Auditory Memory ◽  
Central Component ◽  
Common Descent ◽  
Sensory Modalities ◽  
The Rich ◽  
The Brain

Language comprises a central component of a complex that is sometimes called “the human capacity.” This complex seems to have crystallized fairly recently among a small group in East Africa of whom people are all descendants. Common descent has been important in the evolution of the brain, such that avian and mammalian brains may be largely homologous, particularly in the case of brain regions involved in auditory perception, vocalization and auditory memory. There has been convergent evolution of the capacity for auditory-vocal learning, and possibly for structuring of external vocalizations, such that apes lack the abilities that are shared between songbirds and humans. Language’s recent evolutionary origin suggests that the computational machinery underlying syntax arose via the introduction of a single, simple, combinatorial operation. Further, the relation of a simple combinatorial syntax to the sensory-motor and thought systems reveals language to be asymmetric in design: while it precisely matches the representations required for inner mental thought, acting as the “glue” that binds together other internal cognitive and sensory modalities, at the same time it poses computational difficulties for externalization, that is, parsing and speech or signed production. Despite this mismatch, language syntax leads directly to the rich cognitive array that marks us as a symbolic species.

Visual recovery following optic nerve crush in male and female wild-type and TRIF-deficient mice

2020 ◽  
Vol 38 (5) ◽  
pp. 355-368
Author(s):  
Yimeng Lina Du ◽  
Elena G. Sergeeva ◽  
Donald G. Stein
Keyword(s):  
Optic Nerve ◽  
Inflammatory Response ◽  
Functional Recovery ◽  
Inflammatory Responses ◽  
Optic Nerve Crush ◽  
Optomotor Response ◽  
Nerve Crush ◽  
Inflammatory Damage ◽  
Visual Cortices ◽  
The Brain

Background: There is growing evidence that the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway is implicated in the modulation of neuroinflammation following injuries to the brain and retina. After exposure to injury or to excitotoxic pathogens, toll-like receptors (TLR) activate the innate immune system signaling cascade and stimulate the release of inflammatory cytokines. Inhibition of the TLR4 receptor has been shown to enhance retinal ganglion cell (RGC) survival in optic nerve crush (ONC) and in ischemic injury to other parts of the brain. Objective: Based on this evidence, we tested the hypothesis that mice with the TRIF gene knocked out (TKO) will demonstrate decreased inflammatory responses and greater functional recovery after ONC. Methods: Four experimental groups –TKO ONC (12 males and 8 females), WT ONC (10 males and 8 females), TKO sham (9 males and 5 females), and WT sham (7 males and 5 females) –were used as subjects. Visual evoked potentials (VEP) were recorded in the left and right primary visual cortices and optomotor response were assessed in all mice at 14, 30, and 80 days after ONC. GFAP and Iba-1 were used as markers for astrocytes and microglial cells respectively at 7 days after ONC, along with NF-kB to measure inflammatory effects downstream of TRIF activation; RMPBS marker was used to visualize RGC survival and GAP-43 was used as a marker of regenerating optic nerve axons at 30 days after ONC. Results: We found reduced inflammatory response in the retina at 7 days post-ONC, less RGC loss and greater axonal regeneration 30 days post-ONC, and better recovery of visual function 80 days post-ONC in TKO mice compared to WT mice. Conclusions: Our study showed that the TRIF pathway is involved in post-ONC inflammatory response and gliosis and that deletion of TRIF induces better RGC survival and regeneration and better functional recovery in mice. Our results suggest the TRIF pathway as a potential therapeutic target for reducing the inflammatory damage caused by nervous system injury.

scholarly journals Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

2019 ◽  
Vol 20 (24) ◽  
pp. 6125 ◽  
Author(s):  
Ning Liu ◽  
Yinghua Jiang ◽  
Joon Yong Chung ◽  
Yadan Li ◽  
Zhanyang Yu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Neurovascular Unit ◽  
Annexin A2 ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Endogenous Factors ◽  
The Brain

Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood–brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.

scholarly journals Accessing neuroinflammation sites: Monocyte/neutrophil-mediated drug delivery for cerebral ischemia

2019 ◽  
Vol 5 (7) ◽  
pp. eaau8301 ◽  
Author(s):  
Jia Hou ◽  
Xu Yang ◽  
Shiyi Li ◽  
Zhekang Cheng ◽  
Yuhua Wang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Flow ◽  
Cerebral Ischemia ◽  
Inflammatory Response ◽  
Target Cells ◽  
Ischemic Brain ◽  
Therapeutic Molecules ◽  
Cerebral Parenchyma ◽  
Cell Carriers ◽  
The Brain

Cerebral ischemia (CI) results from inadequate blood flow to the brain. The difficulty of delivering therapeutic molecules to lesions resulting from CI hinders the effective treatment of this disease. The inflammatory response following CI offers a unique opportunity for drug delivery to the ischemic brain and targeted cells because of the recruitment of leukocytes to the stroke core and penumbra. In the present study, neutrophils and monocytes were explored as cell carriers after selectively carrying cRGD liposomes, which effectively transmigrated the blood-brain barrier, infiltrated the cerebral parenchyma, and delivered therapeutic molecules to the injured sites and target cells. Our results showed the successful comigration of liposomes with neutrophils/monocytes and that both monocytes and neutrophils were important for successful delivery. Enhanced protection against ischemic injury was achieved in the CI/reperfusion model. The strategy presented here shows potential in the treatment of CI and other diseases related to inflammation.

Sign in / Sign up

Export Citation Format

Share Document