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Neuroinflammation in Acute Ischemic and Hemorrhagic Stroke

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Abstract

Purpose of Review

This review aims to provide an overview of neuroinflammation in ischemic and hemorrhagic stroke, including recent findings on the mechanisms and cellular players involved in the inflammatory response to brain injury.

Recent Findings

Neuroinflammation is a crucial process following acute ischemic stroke (AIS) and hemorrhagic stroke (HS). In AIS, neuroinflammation is initiated within minutes of the ischemia onset and continues for several days. In HS, neuroinflammation is initiated by blood byproducts in the subarachnoid space and/or brain parenchyma. In both cases, neuroinflammation is characterized by the activation of resident immune cells, such as microglia and astrocytes, and infiltration of peripheral immune cells, leading to the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species. These inflammatory mediators contribute to blood-brain barrier disruption, neuronal damage, and cerebral edema, promoting neuronal apoptosis and impairing neuroplasticity, ultimately exacerbating the neurologic deficit. However, neuroinflammation can also have beneficial effects by clearing cellular debris and promoting tissue repair. The role of neuroinflammation in AIS and ICH is complex and multifaceted, and further research is necessary to develop effective therapies that target this process. Intracerebral hemorrhage (ICH) will be the HS subtype addressed in this review.

Summary

Neuroinflammation is a significant contributor to brain tissue damage following AIS and HS. Understanding the mechanisms and cellular players involved in neuroinflammation is essential for developing effective therapies to reduce secondary injury and improve stroke outcomes. Recent findings have provided new insights into the pathophysiology of neuroinflammation, highlighting the potential for targeting specific cytokines, chemokines, and glial cells as therapeutic strategies.

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Abbreviations

AD:

Alzheimer’s disease

ADPKD:

Autosomal dominant polycystic kidney disease

AIS:

Acute ischemic stroke

AMPA:

a-Amino-3-hydroxy-5-methyl-4 isoxazole-propionic acid

ASCVD:

Atherosclerotic cardiovascular disease

AVMs:

Arteriovenous malformations

BBB:

Blood-brain barrier

BDNF:

Brain-derived neurotrophic factor

CAA:

Cerebral amyloid angiopathy

CBF:

Cerebral blood flow

CCR6:

Chemokine receptor 6

CNS:

Central nervous system

CRP:

C-reactive protein

CSF:

Cerebrospinal fluid

CVD:

Cardiovascular disease

DAMPs:

Danger-associated molecular patterns

EAAT2:

Excitatory amino acid transporter 2

GCS:

Glasgow Coma Scale

GDNF:

Glial cell line-derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

HIF-1α:

Hypoxia-inducible factor-1alpha

HMGB1:

High mobility group box-1

HPA:

Hypothalamic pituitary adrenal

HS:

Hemorrhagic stroke

ICAM:

Intracellular adhesion molecule

ICH:

Intracerebral hemorrhage

ICP:

Intracranial pressure

IFN-γ:

Interferon-gamma

IL-1β:

Interleukin-1beta

IRF:

Interferon regulatory factor

LAA:

Large artery atherosclerosis

LPS:

Lipopolysaccharides

MAC:

Membrane attack complex

MAdCAM-1:

Mucosal vascular adhesion molecule -1

MAPK:

Mitogen-activated protein kinase

MCI:

Mild cognitive impairment

MMPs:

Matrix metalloproteinases

MS:

Multiple sclerosis

NETs:

Neutrophil extracellular traps

NF-Κβ:

Nuclear factor kappa beta

Nrf2:

Nuclear factor erythroid 2-related factor 2

OPN:

Osteopontin

PAMPs:

Pathogen-associated molecular pattern molecules

PDGF:

Platelet-derived growth factor

PECAM-1:

Platelet and endothelial cell adhesion molecule-1

PPAR-γ:

Peroxisome proliferator-activated receptor gamma

PRRs:

Pattern recognition receptors

PSD:

Post-stroke depression

PSF:

Post-stroke fatigue

RAGE:

Receptor for advanced glycation end products

ROS:

Reactive oxygen species

SDF-1:

Stromal cell-derived factor-1

SEFIR:

SEF/IL-17R

SNS:

Sympathetic nervous system

Sox2:

SRY-box 2

SVD:

Small vessel disease

TGF-β:

Transforming growth factor beta

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor-alpha

T-regs:

Regulatory T-cells

VCAM-1:

Vascular cell adhesion molecule-1

VEGF:

Vascular endothelial growth factor

VNS:

Vagus nerve stimulation

vWF:

Von Willebrand factor

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Acknowledgements

The editors would like to thank Dr. John Brust for taking the time to review this manuscript.

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Authors and Affiliations

  1. Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

    Diana L. Alsbrook

  2. Neurological Service, SS Annunziata Hospital, Sulmona, L’Aquila, Italy

    Mario Di Napoli

  3. Department of Neurology, University of Mississippi Medical Center, Jackson, MS, USA

    Kunal Bhatia

  4. Department of Neurology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

    José Biller

  5. Research Unit of Neurology, Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

    Sasan Andalib

  6. Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Archana Hinduja

  7. Department of Neurology, University of Louisville, Louisville, KY, USA

    Roysten Rodrigues

  8. College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    Miguel Rodriguez

  9. Department of Neurology, University of New Mexico, Albuquerque, NM, USA

    Sara Y. Sabbagh, Maryam Hosseini Farahabadi & Afshin A. Divani

  10. Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Magdy Selim

  11. Department of Neurology, Tufts Medical Center, Boston, MA, USA

    Alibay Jafarli

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Diana L. Alsbrook, Mario Di Napoli, Kunal Bhatia, José Biller, Sasan Andalib, Archana Hinduja, Roysten Rodrigues, Miguel Rodriguez; Sara Y. Sabbagh, Magdy Selim, Maryam Hosseini Farahabadi, Alibay Jafarli, and Afshin A. Divani each declare no potential conflicts of interest.

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Alsbrook, D.L., Di Napoli, M., Bhatia, K. et al. Neuroinflammation in Acute Ischemic and Hemorrhagic Stroke. Curr Neurol Neurosci Rep 23, 407–431 (2023). https://doi.org/10.1007/s11910-023-01282-2

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