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Bilirubin and Ischemic Stroke: Rendering the Current Paradigm to Better Understand the Protective Effects of Bilirubin

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Abstract

Novel and innovative methods are critical in fostering new treatments and improving clinical outcomes in patients who suffer from ischemic stroke. Bilirubin has long been considered metabolic waste that can be harmful to the body; however, it is now becoming recognized as one of the body’s most potent antioxidant, anti-inflammatory, and neuroprotective molecules. These properties facilitate bilirubin’s anti-atherogenic effects to impede and prevent the formation of thrombi in ischemic stroke. These functions allow for protection from neuronal injury during an ischemic state and suggest that elevated bilirubin levels may be linked to a lower rate of morbidity and mortality. Therefore, here we discuss the pathophysiology of stroke and the molecular properties of bilirubin to better understand their beneficial relationship. We outline clinical studies looking at the relationship between serum bilirubin levels and ischemic stroke prevalence. At this time, few studies have rigorously looked at the relationship between bilirubin and ischemic stroke, whether it is positive or negative. Thus, rigorous research is needed to provide evidence supporting the current studies, expand on these studies, and facilitate their translation to bedside therapy for patients who suffer from ischemic stroke.

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Abbreviations

AIS:

acute ischemic stroke

CHD:

coronary heart disease

CRP:

C-reactive protein

HDL:

high-density lipoprotein

HO1:

heme oxygenase 1

HR:

hazard ratio

ICAM:

intracellular adhesion molecule

IS:

ischemic stroke

LAA:

large artery atherosclerosis

LACI:

laclunar infarction

LDL:

low-density lipoprotein

MAPK:

mitrogen-activated protein kinase

NADPH:

nicotinamide adenine dinucleotide phosphate

NFĸB:

nuclear factor kappa B cells

OR:

odds ratio

PACI:

partial anterior circulation infarction

POCI:

posterior circulation infarction

PTEN:

phosphatase and tensin homolog

Q:

quartile

SAO:

small-artery occlusion

SCE:

cardioembolic stroke

SD:

standard deviation

SUE:

stroke of undetermined etiology

SNP:

single-nucleotide polymorphisms

TACI:

total anterior circulation infarction

TIA:

transient ischemic attack

TNF:

tumor necrosis factor

UGT:

uridine diphosphate glucuronosyltransferase

VCAM:

vascular cell adhesion protein

GGT:

gamma-glutamyl transpeptidase

UCB:

unconjugated bilirubin.

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Acknowledgements

The authors wish to thank members of the Doré Lab and the University of Florida Center for Translational Research in Neurodegenerative Disease.

Funding

Part of the funding to support this work was provided by grants from the NIH, the AHA, Brain Aneurysm Foundation, and the Department of Anesthesiology.

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Author notes

  1. Mrugesh Thakkar and Jurian Edelenbos contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL, USA

    Mrugesh Thakkar, Jurian Edelenbos & Sylvain Doré

  2. Departments of Neurology, Psychiatry, Pharmaceutics, Psychology, and Neuroscience, University of Florida College of Medicine, 1275 Center Drive, Biomed Science Building J493, PO 100159, Gainesville, FL, 32610, USA

    Sylvain Doré

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Thakkar, M., Edelenbos, J. & Doré, S. Bilirubin and Ischemic Stroke: Rendering the Current Paradigm to Better Understand the Protective Effects of Bilirubin. Mol Neurobiol 56, 5483–5496 (2019). https://doi.org/10.1007/s12035-018-1440-y

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