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Stroke: Cytoprotection, Repair and Regeneration—The Continuum of Patient Care

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Cellular and Molecular Approaches to Regeneration and Repair

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

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Abstract

The ischemic penumbra is now defined as tissue at risk of becoming fully involved in the evolving neurodegenerative process following an embolic stroke. After an ischemic core is quickly developed following vascular occlusion, there is slow spreading of the ischemic injury from the core to areas immediately surrounding the core until full recruitment is achieved. Forty years ago, seminal electrophysiological studies forming the basis of the penumbral hypothesis were conducted in a large animal model, baboons, an animal that is now rarely used in translational stroke research because it can no longer be justified! Thereafter, the rabbit embolic stroke model led the way for approval of Alteplase® (tissue plasminogen activator, tPA, rt-PA) to treat acute ischemic stroke.

Stroke research continues to evolve with the use of rodents primarily mice, rats, Oryctolagus cuniculus (rabbits), and occasionally non-human primates, but recent scientific expert statements have now suggested that non-human primates are not essential for stroke therapy development. One commonality amongst all species used historically is the documented presence of a core and penumbra following vascular occlusion, whether it be an artificial suture or clip occlusion or a blood clot.

This article reviews the historical basis for a few select mechanisms that are currently being targeted for cytoprotection, the rationale for target engagement to arrest penumbral growth and reduce clinical deficits, and it also sets a basis for the future of regeneration strategies to treat stroke patients.

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Abbreviations

ACTION:

Effect of Natalizumab on Infarct Volume in Acute Ischemic Stroke

ALS:

Amyotrophic lateral sclerosis

ATP:

Adenosine triphosphate

AU:

Arbitrary units

ESCAPE:

Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke

EXTEND-IA:

Trial and Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial

FDA:

Food and Drug Administration

FRONTIER:

Field Randomization of NA-1 Therapy in Early Responders

H2O2 :

Hydrogen peroxide

HO•:

Hydroxyl radical

ICB:

Intracerebral

IV:

Intravenous

M1 or M2:

Macrophage

MASTERS:

Multipotent adult progenitor cells in acute ischemic stroke

MR CLEAN:

Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands

mRS:

Modified Rankin scale

Nd:YaG:

Neodymium-doped yttrium aluminum garnet

NADPH:

Nicotinamide adenine dinucleotide phosphate

NADH:

Nicotinamide adenosine dinucleotide

NEST:

NeuroThera® Efficacy and Safety Trial

NIH:

National Institutes of Health

NIHSS:

National Institutes of Health Stroke Scale

NINDS:

National Institute of Neurological Disorders and Stroke

NMDA:

N-methyl-D-aspartate

nNOS:

Neuronal Nitric oxide synthase

OPB:

2-Oxo-3-(phenylhydrazone)-butanoic acid

O2•−:

Superoxide anion radical

PISCES:

Human neural stem cells in patients with chronic ischaemic stroke

PSD-95:

PSD-95 (postsynaptic density protein 95

PDZ1-2:

Postsynaptic density-95, discs large 1, zonula occludens-1

REVASCAT:

Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours

SWIFT PRIME:

Solitaire With the Intention For Thrombectomy as PRIMary Endovascular Treatment

TCA cycle:

Tricarboxylic acid cycle

TIGAR:

TP53-inducible regulator of glycolysis and apoptosis

TLT:

Transcranial laser therapy

tPA:

Tissue plasminogen activator

THRACE:

THRombectomie des Arteres CErebrales

TTC:

Triphenyl tetrazolium chloride

UV:

Ultraviolet

VLA-4:

Very late antigen-4

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Acknowledgments and Funding

This article was written without direct financial support from government sources (PAL). PAL is supported by pharmaceutical industry grants and philanthropic donations. P. Butte is thanked for assistance with NADH measurements.

Conflict of Interest Statements: PAL is Editor-in-Chief, Journal of Neurology & Neurophysiology and Associate Editor, Translational Stroke Research.

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  1. Department of Neurology & Neurosurgery, Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion, Suite 8318, 127 S. San Vicente Blvd, Los Angeles, CA, 90048, USA

    Paul A. Lapchak Ph.D., FAHA

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  1. Paul A. Lapchak Ph.D., FAHA
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Correspondence to Paul A. Lapchak Ph.D., FAHA .

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Editors and Affiliations

  1. Department of Neurology & Neurosurgery, Cedars-Sinai Medical Center, AHSP, Los Angeles, California, USA

    Paul A. Lapchak

  2. Department of Physiology, Loma Linda University, Loma Linda, California, USA

    John H. Zhang

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Lapchak, P.A. (2018). Stroke: Cytoprotection, Repair and Regeneration—The Continuum of Patient Care. In: Lapchak, P., Zhang, J. (eds) Cellular and Molecular Approaches to Regeneration and Repair. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-66679-2_1

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  • DOI: https://doi.org/10.1007/978-3-319-66679-2_1

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