Targeting the Brain: Neuroprotection and Neurorestoration in Ischemic Stroke

Jeffrey L. Saver, M.D., FAHA, FAAN

Disclosures

Pharmacotherapy. 2010;30(7):62S-69S. 

In This Article

Neuroprotection

Neuroprotective therapies for patients with acute ischemic stroke are treatments that enable brain cells to endure reduced blood flow.[1,2] Neuroprotective agents interrupt the cellular, biochemical, and metabolic processes that lead to brain injury during or after exposure to ischemia and encompass a wide and continually expanding array of pharmacologic interventions. As understanding of the pathophysiologic complexity of ischemic brain injury and the ischemic cascade has increased over the past 25 years, the categories of neuroprotective agents have grown to include the following: suppressors of neuronal metabolism, calcium entry blockers, excitotoxic neurotransmission blockers, free radical scavengers, nitric oxide–related interventions, apoptosis inhibitors, hyperpolarization agents that inhibit peri-infarct depolarization, promoters of membrane repair, antiinflammatory and anticytokine agents, and neurotrophic agents.

Although these and additional neuroprotective classes have been effective in reducing infarct size in animal stroke models, the record of neuroprotective agents in human clinical trials has been remarkably disappointing. More than 70 neuroprotective agents have been tested in more than 140 randomized, controlled, clinical trials in acute ischemic stroke, enrolling over 25,000 patients, but no agent was unequivocally beneficial in definitive phase III trials.[3] This daunting record of failure after failure provoked a true Kuhnian scientific crisis in neuroprotection research around the turn of the millennium, with many leading investigators stepping back from studies of individual agents to identify structural defects in the research paradigms that reigned both in basic science laboratories and in translational clinical trials.[1,4] Valuable lessons learned from previous trials have yielded distinctive insights into fundamental mechanisms of ischemic brain injury, novel classes of pharmacologic therapies, more appropriate designs for neuroprotective clinical trials, and novel treatment-delivery strategies.

Delayed time to start of treatment was a particularly crucial defect that hindered all past human clinical trials of neuroprotective drugs. Rodent and nonhuman primate experimental studies suggest the duration of the therapeutic window within which neuroprotective intervention can ameliorate bioenergetic failure in the ischemic penumbra is very brief, generally less than 2–3 hours. Most animal studies of neuroprotective agents initiate therapy within 1–60 minutes after ischemia onset. However, although it is within the first 2 hours of ischemia onset that neuroprotective agents in general are beneficial in focal animal stroke models, no clinical trial of neuroprotective agent enrolled any substantial cohort of patients in this time window. Early neuroprotective trials permitted initiation of therapy at lengthy intervals after symptom onset—up to 48 hours—well after the critical period for stabilizing the penumbral region had ended. More recent trials used shorter entry windows but continued to treat few patients within the first 1 or 2 hours. An analysis of 5345 patients enrolled in six neuroprotective trials performed in the 1990s and 2000s showed that only 0.2% of patients received the study agent in the first hour after symptom onset and only 1.2% in the second hour; 6.3% received the agent in the third hour; and 92.3% were treated beyond 3 hours (Figure 1).[5] Devising methods to safely initiate experimental neuroprotective therapies more quickly is critical if the dramatic benefits of neuroprotective agents evident in the laboratory are to be achieved in human stroke victims.

Figure 1.

Proportions of patients who received the study agent within the acute time window for study enrollment in a pooled analysis of 5345 patients in six large neuroprotective trials in the 1990s and 2000s. The area of each box is proportional to the percentage of patients for each time window. (From reference 5.)

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