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History of Neuroprotection: Trials and Tribulations

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Neuroprotective Therapy for Stroke and Ischemic Disease

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

Abstract

Neuroprotection is a strategy of interference, antagonism, and slowing down the sequence of molecular pathophysiological processes eventually resulting in irreversible cerebral ischemia. Over the past two decades, neuroprotection in ischemic stroke has emerged as a central topic of intense experimental animal studies and clinical trials in humans. Although rigorous animal studies have provided the proof of principle that neuroprotection is achievable, the novel agents and mechanisms investigated in human clinical trials have consistently failed to demonstrate a significant beneficial effect. Here we survey key neuroprotective trials and consider the strengths and shortcomings of these studies. Agents and mechanisms considered include calcium channel blockers, glutamate antagonists, GABA agonists, antioxidants and free radical scavengers, nitric oxide signal-transduction, modulation of inflammation, hemodilution, hypothermia, albumin therapy, and magnesium therapy. These human trials of neuroprotection therapies have been disappointing, unlike successful acute stroke approaches using reperfusion therapies such as thrombolytics or clot-retrieving devices. We highlight how improved clinical trial design and translational strategies and lessons learned from these negative trials will guide future directions including better clinical trial design and patient selection, multiple agent-combination therapies, and pre-hospital intervention.

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Abbreviations

ALIAS:

Albumin in Acute Stroke

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate

ARTIST:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate Receptor Antagonist Treatment in Ischemic Stroke Trial

ASTIN:

Acute Stroke Therapy by Inhibition of Neutrophils

CDP:

Choline-cytidine 5-diphosphocholine

CLASS:

Clomethiazole Acute Stroke Study

DNA:

Deoxyribonucleic acid

Epo:

Erythropoietin

FAST-MAG:

Field Administration of Stroke Therapy-Magnesium

GABA:

Gamma-aminobutyric acid

GAIN:

Glycine Antagonist in Neuroprotection

ICTUS:

International Citicoline Trial on Acute Stroke

ICTuS:

Intravascular Cooling in the Treatment of Stroke

IMAGES:

Intravenous Magnesium Efficacy in Stroke trial

MCA:

Middle cerebral artery

MRI:

Magnetic resonance imaging

mRS:

modified Rankin scale

NIHSS:

National Institutes of Health stroke scale

NMDA:

N-methyl-d-aspartate

PBN:

a-phenyl-N-tert-butyl nitrone

RANTTAS:

Randomized Trial of Tirilazad mesylate in patients with Acute Stroke

SAINT:

Stroke-Acute Ischemic NXY Treatment

STAIR:

Stroke Therapy Academic Industry Roundtable

tPA:

Tissue plasminogen activator

VENUS:

Very Early Nimodipine Use in Stroke

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Authors and Affiliations

  1. Department of Neurology, University of California, Irvine, 200 S. Manchester Ave., Suite 206, Orange, CA, 92868, USA

    Ali Razmara M.D., Ph.D. & Steven C. Cramer M.D., M.M.Sc.

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  1. Ali Razmara M.D., Ph.D.
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  2. Steven C. Cramer M.D., M.M.Sc.
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Correspondence to Ali Razmara M.D., Ph.D. .

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

    Paul A. Lapchak

  2. Loma Linda University School of Medicine, Loma Linda, California, USA

    John H. Zhang

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Razmara, A., Cramer, S.C. (2017). History of Neuroprotection: Trials and Tribulations. In: Lapchak, P., Zhang, J. (eds) Neuroprotective Therapy for Stroke and Ischemic Disease. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-45345-3_5

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