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Neuroprotective Therapies for Spontaneous Intracerebral Hemorrhage

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Abstract

Patients who survive the initial ictus of spontaneous intracerebral hemorrhage (ICH) remain vulnerable to subsequent injury of the perilesional parenchyma by molecular and cellular responses to the hematoma. Secondary brain injury after ICH, which contributes to long-term functional impairment and mortality, has emerged as an attractive therapeutic target. This review summarizes preclinical and clinical evidence for neuroprotective therapies targeting secondary injury pathways following ICH. A focus on therapies with pleiotropic antiinflammatory effects that target thrombin-mediated chemotaxis and inflammatory cell migration has led to studies investigating statins, anticholinergics, sphingosine-1-phosphate receptor modulators, peroxisome proliferator activated receptor gamma agonists, and magnesium. Attempts to modulate ICH-induced blood–brain barrier breakdown and perihematomal edema formation has prompted studies of nonsteroidal antiinflammatory agents, matrix metalloproteinase inhibitors, and complement inhibitors. Iron chelators, such as deferoxamine and albumin, have been used to reduce the free radical injury that ensues from erythrocyte lysis. Stem cell transplantation has been assessed for its potential to enhance subacute neurogenesis and functional recovery. Despite promising preclinical results of numerous agents, their outcomes have not yet translated into positive clinical trials in patients with ICH. Further studies are necessary to improve our understanding of the molecular events that promote damage and inflammation of the perihematomal parenchyma after ICH. Elucidating the temporal and pathophysiologic features of this secondary brain injury could enhance the clinical efficacy of neuroprotective therapies for ICH.

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Abbreviations

mRS:

Modified Rankin Scale score

ICH:

Intracerebral hemorrhage

PHE:

Perihematomal edema

NIHSS:

National Institutes of Health Stroke Scale

NMDA:

N-methyl-D-aspartate

BBB:

Blood-brain barrier

NSAID:

Non-steroidal anti-inflammatory drug

CNS:

Central nervous system

MMP:

Matrix metalloproteinase

MMP-3:

Matrix metalloproteinase 3

MMP-9:

Matrix metalloproteinase 9

MMP-3:

Matrix metalloproteinase 3

PHE:

Perihematomal edema

PI3K-Akt:

Phosphoinositide 3-kinase-protein kinase B

ROS:

Reactive oxygen species

JAK-STAT:

Janus kinase-Signal transducer and activator of transcription protein

NF-kB:

Nuclear factor kappa light chain enhancer of activated B cells

C3a:

Complement component 3a

C5a:

Complement component 5a

IL-1β:

Interleukin 1 Beta

IL-18:

Interleukin 18

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Funding

This study received no funding.

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Author notes

  1. Kathryn N. Kearns and Natasha Ironside have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA

    Kathryn N. Kearns, Natasha Ironside, Min S. Park & Ching-Jen Chen

  2. Department of Neurology, University of Virginia Health System, Charlottesville, VA, USA

    Bradford B. Worrall & Andrew M. Southerland

  3. Department of Neurosurgery, University of Louisville Health System, Louisville, KY, USA

    Dale Ding

Authors
  1. Kathryn N. Kearns
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  2. Natasha Ironside
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  6. Ching-Jen Chen
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Contributions

KNK performed acquisition of data. KNK, NI performed drafting the article. NI, C-JC performed analysis and interpretation of data. C-JC, DD performed conception and design. NI, MSP, BBW, AMS, C-JC, DD performed revising the article critically for important intellectual content, and the final manuscript was approved by all authors.

Corresponding author

Correspondence to Dale Ding.

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Conflicts of interest

Dr. Ironside has a patent 62/942,194 pending, and a patent 62/942,195 pending. Dr. Southerland reports grants from American Heart Association/American Stroke Association (AHA/ASA) Innovative Project Award, grants from National Science Foundation's Innovation Corps (NSF I-Corps) Program, grants from University of Virginia (UVA) Coulter Translational Research Award, outside the submitted work. In addition, Dr. Southerland has a patent 62/620,096 pending, and a patent Patent Cooperation Treaty (PCT)/US19/14605 pending. Otherwise, the remaining authors report no conflicts of interest to disclose.

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Kearns, K.N., Ironside, N., Park, M.S. et al. Neuroprotective Therapies for Spontaneous Intracerebral Hemorrhage. Neurocrit Care 35, 862–886 (2021). https://doi.org/10.1007/s12028-021-01311-3

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  • DOI: https://doi.org/10.1007/s12028-021-01311-3

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