Brain protection from focal or global cerebral ischemia is not new, not innovative, and so far, mostly not successful. There have been many methods and agents tried in an attempt to produce neuroprotection from cerebral ischemia: hypothermia, anesthetics, free radical scavengers, excitatory amino acid antagonists, calcium channel blockers, ionic pump modulators, growth factors, heparinization, antineutrophil/platelet factors, sex steroids, and genes and gene products. There are hundreds, perhaps thousands of neuroprotective drugs that have been used in animal models. So, if you were a mouse or a rat, and experienced a stroke or cardiac arrest, we would know just what to do for you. But, essentially none of these pharmacological agents have demonstrated usefulness in humans even though they have been shown to be successful in preclinical animal trials. What could account for this and why do we not have a “magic bullet”?
One issue is that there are several important mechanisms of injury from focal and global cerebral ischemia, and the agents mentioned above usually work only on 1 potential mechanism. For example, ischemia can produce free radicals, result in the release of excitotoxins, and release mediators of inflammation, and there are other mechanisms of injury as well. All of these mechanisms of injury can result in neuronal cell death. Because there are multiple mechanisms of injury, it is likely that there are multiple mechanisms of neuroprotection. None of the agents mentioned above can affect all mechanisms of injury at once or at the appropriate time after injury. Another issue is that there is a temporal sequence of injury after ischemia. For example, excitotoxicity occurs very quickly, in minutes or hours after the ischemia. Inflammatory injury or apoptotic injury may not occur until hours or even days after the injury. There is even a temporal sequence of gene expression such that heat shock proteins and early genes are expressed early after the ischemia, whereas growth factor genes are expressed days after the injury. Thus, the pharmacological agents must be administered at the appropriate time to result in neuroprotection.
There are other issues concerning drug dose and time of administration of the drug which can determine neuroprotection efficacy. A dose of drug that is effective in a mouse may not be the correct effective dose in the human. The window of opportunity in a mouse also may not be the correct window in the human. Combination therapy also needs to be attempted in humans. In addition, in humans there may be a genetic predisposition for injury from ischemia, and gender differences. Issues related to trial design and analysis also must be considered. We must also consider that we work mostly with normal, young, healthy animals, whereas in the human population this is not true. Finally, we must also ask the question of whether the animal models of ischemia we use accurately reflect ischemic disease in humans.
In this neuroprotection session, we will address several novel mechanisms of protection from ischemia. Dr Anne Comi will address ischemic injury and neuroprotection in immature brain and will discuss new approaches to reduce apoptosis (prevention of apoptosis and the erythropoietin trial in newborns). Dr Midori Yenari will speak about hypothermic neuroprotection for cerebral ischemia and will discuss the status of clinical hypothermia and challenges in its clinical application. Dr Kyra Becker will discuss immune tolerance therapy for stroke and attempt to answer the question whether modulation of the postischemic immune response can improve stroke outcome? Finally, Dr Daniel Laskowitz will address neuroprotection in subarachnoid hemorrhage and ask the question of whether vasospasm is a good therapeutic target in subarachnoid hemorrhage?
- Received July 29, 2010.
- Accepted August 10, 2010.