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Neuroprotection against Cerebral Ischemia

A Review of Animal Studies and Correlation withHuman Trial Results

S. JONAS,a,c V. AYIGARI,a D. VIERA,b AND P. WATERMANa

aDepartment of Neurology and bMedical Library, New York University School of Medicine, New York, New York 10016, USA

“Does effect of a neuroprotective agent on volume of experimental animal cerebralinfarct predict effect of the agent on clinical outcome in human stroke?” We ad-dressed this subject in a previous review bearing this title.1 We now extend this re-view to include the experimental animal studies published through August 1998, andthe results of human trials of 12 of these agents.

Among the 12 agents tried in humans, only thrombolytic treatment with tissueplasminogen activator (tPA) given in the first 3 hours after ischemic stroke has beenaccepted by the Food and Drug Administration (FDA) to be superior to placebo,based on clinical stroke outcomes in the 3-hour window National Institute of Neu-rological Disorders and Stroke/NIH (NINDS) trial. The FDA has not accepted anyof the other 11 agents as useful for ischemic stroke.

We present graphically the animal results (FIG. 1): x-axis: time in minutes frominduction of focal ischemia to first treatment (prophylactic treatments are assignedto −1 minute, and immediate postischemia treatments to +1 minute); y-axis: size oftreated infarct relative to size of control infarct (0–100%; treated infarcts >controlsize are valued at 100%). The regression line for the nine results of the various ex-perimental thrombolysis studies runs from approximately 20% at 0 time to approxi-mately 50% at 6 hours (95% confidence curves are provided). For 10 agents, pluslow molecular weight herapin (LMWH) used in low doses, all results of administra-tion after 30 minutes lie in the “no-fly zone” above the upper 95% confidence curvefor thrombolysis. LMWH in high doses (10 to 30 times the human trial doses) gaveanimal results (one study) in the thrombolysis range.

DISCUSSION

The thrombolysis results show that ischemic brain tissue in animals can be sal-vaged even up to 6 hours by restoration of blood flow. With the exception of highdose LMWH, there is no evidence that any so-called neuroprotective drug tested inhumans can produce salvage in animals comparable to that seen with thrombolysis,if first administration is at more than 30 minutes after onset of focal ischemia.

cCorresponding author: Saran Jonas, M.D., Professor of Clinical Neurology, NYU School ofMedicine, 550 First Avenue, New York, NY 10016. Phone, 212/263-7202; fax, 212/263-8228.

3JONAS et al.: NEUROPROTECTION AGAINST CEREBRAL ISCHEMIA

With regard to the predictive value of infarct size in animals for clinical outcomein human stroke patients, the implications are clear:

• None of the regimens used in human trials came close in animals to producingthe results seen in animal thrombolysis studies.

• An agent with poorer animal results than thrombolysis for a given time of firsttreatment will fail in humans if given at that time or later.

• Of the 11 agents studied in humans and animals, only LMWH in high doses isworthy of further investigation.

REFERENCE

1. JONAS, S., A.Q. TRAN, E. EISENBERG, M. AZAM, D. VIERA & S. GRUMET. 1997. Doeseffect of a neuroprotective agent on volume of experimental animal cerebral infarctpredict effect of the agent on clinical outcome in human stroke? Ann. N.Y. Acad. Sci.825: 281–287.

FIGURE 1. Clinically studied agents versus thrombolysis.