Published Online
on November 29, 2007

A more recent version of this article appeared on January 1, 2008

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Submitted on May 9, 2007
Revised on July 17, 2007
Accepted on August 1, 2007

The 2007 Feinberg Lecture. A New Road Map for Neuroprotection

Geoffrey A. Donnan MD, FRACP^*

From the National Stroke Research Institute, Austin Health, University of Melbourne, Heidelberg Heights, Australia.

^* To whom correspondence should be addressed. E-mail: gdonnan{at}unimelb.edu.au.

Background and Purpose—There have now been numerous phase III trials of neuroprotection that have failed to live up to the expectations created by preclinical testing in animal models, the most recent of which was the second pivotal trial of the spin trap agent NXY-059. We have reached a stage at which research in this area should stop altogether or radical new approaches adopted. The purpose of this article is to review how we reached this stage and make recommendations for a new approach to neuroprotection research.

Methods—The background to neuroprotection research is reviewed and its problems are highlighted based on the research of others and of our own research group. From this, a series of questions are posed that require answers if the field is to progress. A road map for future research is then proposed.

Results—The road map involves the following steps for putative neuroprotectants: (1) better proof of efficacy in animal models; (2) in vivo evidence of efficacy in human tissue using cell cultures or brain slices; (3) in vivo studies of their distribution in the normal and ischemic human brain, particularly focusing on the ischemic penumbra; (4) demonstration of efficacy in novel human models of cerebral ischemia; and (5) phase II and III clinical trails with penumbral selection using imaging techniques.

Conclusions—The accumulated evidence suggests that neuroprotection failure in clinical trial is due to identifiable preclinical and clinical factors. Neuroprotection research should be pursued but with a very different and more rigorous approach.

Key words: animal stroke models • brain imaging • brain slices • cell cultures • cerebral ischemia • clinical trials • ischemic cascade • ischemic penumbra • neuroprotection • stroke

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