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Therapeutic Strategies Harnessing Oxidative Stress to Treat Stroke

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Abstract

Oxidative stress is a major mechanism responsible for damage in ischemic stroke. Other than tissue plasminogen activator and antiplatelet agents, no pharmacological interventions have been translated into an effective treatment for stroke. As yet, there have been no unequivocally successful clinical applications of antioxidants to scavenge reactive oxygen or nitrogen species (ROS/RNS) in stroke, with some even suggested to have a detrimental effect.

Edaravone, a low-molecular weight scavenger of hydroxyl, peroxyl, and superoxide radicals that readily crosses the blood–brain barrier, was approved in 2001 in Japan for use in ischemic stroke within 24 h of the attack. However, other notable compounds such as NXY-059, a nitrone with free radical scavenging ability that fufilled nearly all of the Stroke Therapy Industry Roundtable (STAIR) criteria, still failed to make it to the clinic. NADPH oxidase inhibitors have shown promise, but are yet to be validated in clinical trials. Any prospective neuroprotective agent targeting oxidative stress would buy time to delay the ischaemic cascade, pending imaging to permit definitive restoration of blood flow.

A small molecule inhibitor of oxidative stress is unlikely to provide the panacea for ischemic stroke. Instead, targeting the ischemic cascade and resultant oxidative stress at its origin, in combination with optimization of physiological parameters and consideration of the neurovascular unit as a whole, is likely to be more effective than mere damage limitation. This chapter will discuss recent and current experimental and clinical data on therapeutic strategies targeting oxidative stress in stroke.

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Abbreviations

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ASA:

Acetylsalicylic acid

AT-1:

Angiotensin-1 receptor 1

AVASAS:

Aspirin versus ascorbic acid plus aspirin in stroke

DNA:

Deoxyribonucleic acid

EAAT-1:

Excitatory amino acid transporter-1

HMG-CoA:

3-Hydroxy-3-methyl-glutaryl-CoA reductase

HO∙ :

Hydroxyl radical

H2O2 :

Hydrogen peroxide

mRS:

Modified Rankin Scale

NADPH:

Nicotinamide adenine dinucleotide phosphate

NDMA:

N-Methyl-d-aspartate

NIHSS:

National Institutes of Health Stroke Scale

NO:

Nitric oxide

NOS:

Nitric oxide synthase

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

rtPA:

Recombinant tissue plasminogen activator

SOD:

Superoxide dismutase

VISTA:

Virtual International Stroke Trials Archive

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Authors and Affiliations

  1. Acute Stroke Programme, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK

    Gina Hadley M.R.C.P., Ain A. Neuhaus B.A. & Alastair M. Buchan F.Med.Sci.

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  1. Gina Hadley M.R.C.P.
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  2. Ain A. Neuhaus B.A.
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  3. Alastair M. Buchan F.Med.Sci.
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Correspondence to Alastair M. Buchan F.Med.Sci. .

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Editors and Affiliations

  1. Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA

    Martin Rodriguez-Porcel

  2. University of Mississippi, Jackson, Mississippi, USA

    Alejandro R. Chade

  3. Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA

    Jordan D. Miller

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Hadley, G., Neuhaus, A.A., Buchan, A.M. (2017). Therapeutic Strategies Harnessing Oxidative Stress to Treat Stroke. In: Rodriguez-Porcel, M., Chade, A., Miller, J. (eds) Studies on Atherosclerosis. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Boston, MA. https://doi.org/10.1007/978-1-4899-7693-2_7

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