Research Into Neuroprotection Must Continue … but With a Different Approach
Geoffrey A. Donnan MD, FRACP Stephen M. Davis MD, FRACP Section Editors:
Neuroprotective agents disrupting the ischemic cascade and salvaging the ischemic penumbra are being explored as a potential therapeutic option for stroke. Although a number of agents are neuroprotective in animal studies, none of the human trials have been positive, with the exception of the SAINT I trial.1 Unfortunately, the follow-up SAINT II trial had a negative result,2 and a great deal of pessimism regarding the future of neuroprotection has been generated. However, before abandoning neuroprotection as a strategy, it is important to examine where research in neuroprotection has brought us and how we can better design future animal and clinical studies.
The main reason for failure has been poor translation from animal studies to clinical trials. Clinical trials often had prolonged therapeutic windows, small sample sizes, and failed to achieve adequate plasma levels of study medications. These problems lead to the Stroke Therapy Academic Industry Roundtable (STAIR) recommendations,3,4 which have greatly improved the methodology of stroke trials. Preclinical development is more rigorous, and clinical trials are attempting to replicate the laboratory, with shorter therapeutic windows and by standardizing stroke severity.
The Future of Neuroprotection
Our understanding of the ischemic cascade needs to be further refined, especially in the complex setting of human ischemic stroke. Specific pathways need better characterization, particularly taking into account how factors such as age or comorbidities may influence the cascade. The targets of many of the neuroprotective medications are often speculative, and more effort is needed to determine their precise mechanisms of action. We also should analyze how reducing activity in one of the pathways may influence other pathways within the cascade.
Although translational research has improved, current recommendations should be reexamined. NXY-059 met most of the STAIR criteria, but concerns remained, including its ability to cross the blood-brain barrier.5 Investing more time and resources into the animal phase of drug development will be valuable in the long run. This will involve studying animals which more closely mimic human ischemic stroke, such as aged primates with comorbidities like diabetes and hypertension.
In translating animal research to clinical trials, another major difficulty has been using consistent outcome measures. In clinical trials, not only is there a change in species, but whereas animal studies use infarct volume as the outcome measure, clinical trials focus on functional outcomes. As an intermediate step, to more closely replicate the animal situation in which the agent shows effectiveness, we should study smaller groups of patients for changes in infarct volume, based on MRI. In these intermediate studies, we can also select patients with a large volume of ischemic penumbra, as to maximize the potential benefit. To do this, better identification of the ischemic penumbra is needed and is a research priority. Diffusion-perfusion mismatch on MRI can provide a rough estimate of penumbral volume and may be a currently usable surrogate marker while other more accurate techniques are found.6 If these smaller intermediate trials are positive, we can then proceed onto larger trials, which allows for better utilization of resources.
Our expectation for the role of neuroprotection needs to be reassessed. Decreased cerebral blood flow is the primary initiating event causing cerebral damage, and unless increased perfusion of the ischemic penumbra occurs, the multiple pathways of the ischemic cascade will eventually prevail. Also, without adequate perfusion, it is difficult to achieve sufficient concentrations of neuroprotective medications in the penumbral tissue. Supporting this is the observation that many of the neuroprotective agents are more efficacious in transient occlusion models of stroke.7 Neuroprotective agents may slow down the ischemic cascade, allowing valuable time for reperfusion strategies to be initiated. Thus, neuroprotective therapies should be thought of more as an adjunct to reperfusion, producing either increased efficacy, prolonging time windows, or increased safety of these agents. To effectively stall the ischemic cascade, these therapies have to be initiated quickly. The FAST-MAG protocol is a exciting concept where the magnesium loading dose and infusion are being initiated in the ambulance within minutes to hours after onset of symptoms.8 Also, neuroprotective agents usually target only single or limited aspects of the ischemic cascade. The ischemic cascade has multiple pathways by which it can lead to damage, and it is unlikely that targeting a single aspect of the cascade will be efficacious. One strategy to overcome this may be to target several pathways simultaneously by combining multiple neuroprotective agents acting on different points, thereby halting the majority of the ischemic cascade and resultant damage.
Thus, we should reflect on the history of neuroprotection research and acknowledge that, although the breakthrough we are seeking has not been achieved, steady advancement, particularly regarding the methodology of conducting translational research, has occurred. Further refinement and new approaches are now needed, and we must be patient to discover innovative ways to improve outcomes in this debilitating condition.
Sources of Funding
A. Shuaib has received funds from AstraZeneca, Pfizer, Sanofi, BI, Merck, Roche and Sevier as honorarium and for his research.
- Received May 28, 2007.
- Accepted May 30, 2007.
Shuaib A LK, Grotta J, Lyden P, Davalos A, Davis SM, Diener HC, Wasiewski W, Wilmington DE, Ashwood T, Hardemark HG, Emeribe U for the SAINT investigators. Saint ll: Results of the second randomized, multicenter, placebo-controlled, double-blind study of nxy-09 treatment in patients with acute ischemic stroke. International Stroke Conference. 2007.
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