scholarly journals Intranasal Salvinorin A Improves Long-term Neurological Function via Immunomodulation in a Mouse Ischemic Stroke Model

2021 ◽  
Author(s):  
Dilidaer Misilimu ◽  
Wei Li ◽  
Di Chen ◽  
Pengju Wei ◽  
Yichen Huang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Immune Cells ◽  
Intranasal Administration ◽  
Neurological Function ◽  
Salvinorin A ◽  
Stroke Model ◽  
Peripheral Immune Cells ◽  
The Brain

AbstractSalvinorin A (SA), a highly selective kappa opioid receptor agonist, has been shown to reduce brain infarct volume and improve neurological function after ischemic stroke. However, the underlying mechanisms have not been fully understood yet. Therefore, we explored whether SA provides neuroprotective effects by regulating the immune response after ischemic stroke both in the central nervous system (CNS) and peripheral circulation. In this study, adult male mice were subjected to transient Middle Cerebral Artery Occlusion (tMCAO) and then were treated intranasally with SA (50 μg/kg) or with the vehicle dimethyl sulfoxide (DMSO). Multiple behavioral tests were used to evaluate neurofunction. Flow cytometry and immunofluorescence staining were used to evaluate the infiltration of peripheral immune cells into the brain. The tracer cadaverine and endogenous immunoglobulin G (IgG) extravasation were used to detect blood brain barrier leakage. We observed that SA intranasal administration after ischemic stroke decreased the expression of pro-inflammatory factors in the brain. SA promoted the polarization of microglia/macrophages into a transitional phenotype and decreased the pro-inflammatory phenotype in the brain after tMCAO. Interestingly, SA treatment scarcely altered the number of peripheral immune cells but decreased the macrophage and neutrophil infiltration into the brain at 24 h after tMCAO. Furthermore, SA treatment also preserved BBB integrity, reduced long-term brain atrophy and white matter injury, as well as improved the long-term neurofunctional outcome in mice. In this study, intranasal administration of SA improved long-term neurological function via immuno-modulation and by preserving blood–brain barrier integrity in a mouse ischemic stroke model, suggesting that SA could potentially serve as an alternative treatment strategy for ischemic stroke. Graphic Abstract

scholarly journals New Insight Into Neutrophils: A Potential Therapeutic Target for Cerebral Ischemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Ran Chen ◽  
Xu Zhang ◽  
Lijuan Gu ◽  
Hua Zhu ◽  
Yi Zhong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Immune Cells ◽  
Immune Cell ◽  
Ischemic Injury ◽  
Functional Differentiation ◽  
Permanent Disability ◽  
Targeted Interventions ◽  
Peripheral Immune Cells ◽  
The Brain

Ischemic stroke is one of the main issues threatening human health worldwide, and it is also the main cause of permanent disability in adults. Energy consumption and hypoxia after ischemic stroke leads to the death of nerve cells, activate resident glial cells, and promote the infiltration of peripheral immune cells into the brain, resulting in various immune-mediated effects and even contradictory effects. Immune cell infiltration can mediate neuronal apoptosis and aggravate ischemic injury, but it can also promote neuronal repair, differentiation and regeneration. The central nervous system (CNS), which is one of the most important immune privileged parts of the human body, is separated from the peripheral immune system by the blood-brain barrier (BBB). Under physiological conditions, the infiltration of peripheral immune cells into the CNS is controlled by the BBB and regulated by the interaction between immune cells and vascular endothelial cells. As the immune response plays a key role in regulating the development of ischemic injury, neutrophils have been proven to be involved in many inflammatory diseases, especially acute ischemic stroke (AIS). However, neutrophils may play a dual role in the CNS. Neutrophils are the first group of immune cells to enter the brain from the periphery after ischemic stroke, and their exact role in cerebral ischemia remains to be further explored. Elucidating the characteristics of immune cells and their role in the regulation of the inflammatory response may lead to the identification of new potential therapeutic strategies. Thus, this review will specifically discuss the role of neutrophils in ischemic stroke from production to functional differentiation, emphasizing promising targeted interventions, which may promote the development of ischemic stroke treatments in the future.

scholarly journals Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 767
Author(s):  
Courtney Davis ◽  
Sean I. Savitz ◽  
Nikunj Satani
Keyword(s):  
Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Neurovascular Unit ◽  
Culture Conditions ◽  
Therapeutic Effects ◽  
Stroke Treatment ◽  
Inflammatory Molecules ◽  
The Brain

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

Peripheral immune cells infiltrate into sites of secondary neurodegeneration after ischemic stroke

2018 ◽  
Vol 67 ◽  
pp. 299-307 ◽  
Author(s):  
K.A. Jones ◽  
S. Maltby ◽  
M.W. Plank ◽  
M. Kluge ◽  
M. Nilsson ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Immune Cells ◽  
Peripheral Immune Cells

Neutrophil affinity for PGP and HAIYPRH (T7) peptide dual-ligand functionalized nanoformulation enhances the brain delivery of tanshinone IIA and exerts neuroprotective effects against ischemic stroke by inhibiting proinflammatory signaling pathways

2018 ◽  
Vol 42 (23) ◽  
pp. 19043-19061
Author(s):  
Yutao Li ◽  
Chiying An ◽  
Danan Han ◽  
Yanxin Dang ◽  
Xin Liu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Physicochemical Properties ◽  
Signaling Pathways ◽  
Blood Brain Barrier ◽  
Tanshinone Iia ◽  
Brain Barrier ◽  
Brain Delivery ◽  
Neuroprotective Effects ◽  
The Poor ◽  
The Brain

A great challenge to the therapy of ischemic stroke is the poor physicochemical properties and inability of the drug to cross the blood–brain barrier (BBB).

scholarly journals Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

2019 ◽  
Vol 11 ◽  
pp. 117957351984065 ◽  
Author(s):  
Divine C Nwafor ◽  
Allison L Brichacek ◽  
Afroz S Mohammad ◽  
Jessica Griffith ◽  
Brandon P Lucke-Wold ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
The United States ◽  
Brain Barrier ◽  
Blood Brain ◽  
Systemic Inflammatory Disease ◽  
Sepsis Survivors ◽  
The Brain

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors.

scholarly journals Tracking elemental changes in an ischemic stroke model with X-ray fluorescence imaging

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
M. J. Pushie ◽  
N. J. Sylvain ◽  
H. Hou ◽  
S. Caine ◽  
M. J. Hackett ◽  
...  
Keyword(s):  
Cellular Response ◽  
Time Course ◽  
Parameter Method ◽  
Stroke Severity ◽  
Stroke Model ◽  
Post Stroke ◽  
Cellular Events ◽  
Developed Nations ◽  
The Brain

Abstract Stroke is a leading cause of long-term disability in adults and a leading cause of death in developed nations. The cascade of cellular events and signalling that occur after cerebral ischemia are complex, however, analyzing global element markers of metabolic state affords the means to monitor stroke severity, status of injury, and recovery. These markers provide a multi-parameter method for assessing changes through the post-stroke time course. We employ synchrotron-based elemental mapping to follow elemental changes in the brain at 1 h, 1-, 2-, and 3-days, and at 1-, 2-, 3-, and 4-weeks post-stroke in a photothrombotic stroke model in mice. Our analysis reveals a highly consistent metabolic penumbra that can be readily identified based on the level of dysregulated potassium and other key elements. Maps of elemental distributions are also useful to demarcate events in the cellular response to the inflammatory cascade, including ion dysregulation, recruitment of cells to the lesion, and glial scar formation.

Can the Use of Oral Minocycline Improve Ischemic Stroke Outcomes?

2008 ◽  
Vol 21 (2) ◽  
pp. 159-164
Author(s):  
Kathy B. Lee
Keyword(s):  
United States ◽  
Ischemic Stroke ◽  
The United States ◽  
Sudden Onset ◽  
Pharmacological Agents ◽  
Stroke Outcomes ◽  
Stroke Treatment ◽  
The Brain ◽  
Brain Ischemic Stroke

Cerebrovascular accident (CVA), also known as ischemic stroke, is the sudden onset of neurologic deficit attributable to a focal vascular cause.1 It is the third leading cause of death, with the death rate being reported as 50.0 (per 100,000 population) in the United States in 2004.2 It is also a leading cause for serious, long-term disability in the United States. While there are various causes, the large majority of strokes result from either global or focal ischemia of the brain. Ischemic stroke accounts for 87% of all strokes, while intracerebral and subarachnoid hemorrhage makes up the remainder. 2 Currently, the primary pharmacological agents used in stroke treatment are thrombolytics, not without limitations, however, and antiplatelet therapy. 3 Minocycline, a semisynthetic tetracycline antibiotic, has recently gained attention as a neuroprotective agent. A recent study evaluated the use of minocycline in the treatment of acute stroke and demonstrated promising results.4 A review of the mechanisms of action and data presented in past studies will be examined to evaluate the efficacy and clinical impact of minocycline in the treatment of acute ischemic stroke.

scholarly journals Aquaporin-4 Expression during Toxic and Autoimmune Demyelination

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2187
Author(s):  
Sven Olaf Rohr ◽  
Theresa Greiner ◽  
Sarah Joost ◽  
Sandra Amor ◽  
Paul van der Valk ◽  
...  
Keyword(s):  
Immune Cells ◽  
Water Channel ◽  
Staining Intensity ◽  
Brain Parenchyma ◽  
Aquaporin 4 ◽  
Aqp4 Expression ◽  
Humoral Immune ◽  
Autoimmune Demyelination ◽  
Peripheral Immune Cells ◽  
The Brain

The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood–brain interface. Following the discovery that AQP4 is a possible autoantigen in neuromyelitis optica, the function of AQP4 in health and disease has become a research focus. While several studies have addressed the expression and function of AQP4 during inflammatory demyelination, relatively little is known about its expression during non-autoimmune-mediated myelin damage. In this study, we used the toxin-induced demyelination model cuprizone as well as a combination of metabolic and autoimmune myelin injury (i.e., Cup/EAE) to investigate AQP4 pathology. We show that during toxin-induced demyelination, diffuse AQP4 expression increases, while polarized AQP4 expression at the astrocyte endfeet decreases. The diffuse increased expression of AQP4 was verified in chronic-active multiple sclerosis lesions. Around inflammatory brain lesions, AQP4 expression dramatically decreased, especially at sites where peripheral immune cells penetrate the brain parenchyma. Humoral immune responses appear not to be involved in this process since no anti-AQP4 antibodies were detected in the serum of the experimental mice. We provide strong evidence that the diffuse increase in anti-AQP4 staining intensity is due to a metabolic injury to the brain, whereas the focal, perivascular loss of anti-AQP4 immunoreactivity is mediated by peripheral immune cells.

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