Understanding history, and not repeating it. Neuroprotection for acute ischemic stroke: from review to preview

Stephen Grupke; Jason Hall; Michael Dobbs; Gregory J Bix; Justin F Fraser

doi:10.1016/j.clineuro.2014.11.013

Understanding history, and not repeating it. Neuroprotection for acute ischemic stroke: from review to preview

Clin Neurol Neurosurg. 2015 Feb:129:1-9. doi: 10.1016/j.clineuro.2014.11.013. Epub 2014 Dec 3.

Authors

Stephen Grupke¹, Jason Hall¹, Michael Dobbs², Gregory J Bix³, Justin F Fraser⁴

Affiliations

¹ Department of Neurosurgery, University of Kentucky, Lexington, USA.
² Department of Neurology, University of Kentucky, Lexington, USA.
³ Department of Neurology, University of Kentucky, Lexington, USA; Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA.
⁴ Department of Neurosurgery, University of Kentucky, Lexington, USA; Department of Neurology, University of Kentucky, Lexington, USA; Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA; Department of Radiology, University of Kentucky, Lexington, USA. Electronic address: jfr235@uky.edu.

PMID: 25497127
DOI: 10.1016/j.clineuro.2014.11.013

Abstract

Background: Neuroprotection for ischemic stroke is a growing field, built upon the elucidation of the biochemical pathways of ischemia first studied in the 1970s. Beginning in the early 1990s, means by which to pharmacologically intervene and counteract these pathways have been sought, though with little clinical success. Through a comprehensive review of translations from laboratory to clinic, we aim to evaluate individual mechanisms of action, while highlighting potential barriers to success that will guide future research.

Methods: The MEDLINE database and The Internet Stroke Center clinical trials registry were queried for trials involving the use of neuroprotective agents in acute ischemic stroke in human subjects. For the purpose of the review, neuroprotective agents refer to medications used to preserve or protect the potentially ischemic tissue after an acute stroke, excluding treatments designed to re-establish perfusion. This excludes mechanical or pharmacological thrombolytics, anti-thrombic medications, or anti-platelet therapies.

Results: This review summarizes previously trialed neuroprotective agents, including but not limited to glutamate neurotransmission blockers, anti-oxidants, GABA agonists, leukocyte migration blockers, various small cation channel modulators, narcotic antagonists, and phospholipid membrane stabilizers. We outline key biochemical steps in ischemic injury that are the proposed areas of intervention. The agents, time to administration of therapeutic agent, follow-up, and trial results are reported.

Discussion: Stroke trials in humans are burdened with a marked heterogeneity of the patient population that is not seen in animal studies. Also, trials to date have included patients that are likely treated at a time outside of the window of efficacy for neuroprotective drugs, and have not effectively combined thrombolysis with neuroprotection. Through an evaluation of the accomplishments and failures in neuroprotection research, we propose new methodologies, agents, and techniques that may provide new routes for success.

Keywords: Acute stroke; Angiography; Brain ischemia; Drug trials; Neuroprotection.

Publication types

Review

MeSH terms

Animals
Apoptosis / drug effects*
Apoptosis / physiology
Brain Ischemia / therapy*
Fibrinolytic Agents / therapeutic use
Humans
Neuroprotective Agents / therapeutic use*
Stroke / therapy*
Thrombolytic Therapy*

Substances

Fibrinolytic Agents
Neuroprotective Agents