Repetitive Hypoxia Extends Endogenous Neurovascular Protection for Stroke
In the vast majority of individuals, stroke occurs without warning. However, specific subpopulations are known to be at a significantly higher risk for stroke than the general population. If we could treat individuals in these groups in such a way that, if they did suffer a stroke, the resulting damage would be considerably reduced, then significant reductions in stroke morbidity and mortality could be realized.
A new study from our group at Washington University School of Medicine in St. Louis provides data based on studies in mice, supporting the notion that this kind of extended, long-term "tolerance" to stroke is indeed possible. The treatment affording such prolonged neuroprotection is founded on Hippocrates' principle of similia similibus curentur, or "like is cured by like." In other words, we need to hurt the brain (a little bit) in order to make it stronger. Such an approach has come to be called "preconditioning."
Preclinical studies of preconditioning-induced stroke tolerance, wherein a robustly injury-resistant phenotype is achieved in the brain by challenging the animal or tissue with a noninjurious but stressful stimulus, are now entering their third decade. The importance of elucidating the endogenous, epigenetic mechanisms that are capable of protecting the brain from stroke has certainly drawn its share of advocates over this time, in part because we still lack a clinically approved treatment for stroke based on therapies designed to block brain injury pathways. Enhancing Mother Nature's built-in protective mechanisms is a fundamentally different way to think about stroke therapeutics. But dimming the excitement for translating stroke preconditioning successes in animals to our patients has been the predictably short therapeutic window of tolerance so induced: Despite a variety of different stressors being able to elicit an ischemia-tolerant phenotype in quite a number of distinct stroke models and species, the duration of preconditioning-mediated tolerance lasts only a couple of days.
However, in our work with mice, we discovered that by repetitive presentations of the preconditioning stimulus – in our case, mild systemic hypoxia – the period of ischemic tolerance could be extended from days to months (after the last stimulus). This likely reflects a unique kind of neurovascular plasticity, wherein gene expression changes triggered in response to a stimulus train persist long after the stimulus is withdrawn. The distinct patterns of repetitive stimulation that contribute to the encoding of memory and the neurochemistry of addiction/withdrawal are probably valid cellular-molecular correlates.
A Look at Exercise and Erythropoietin
At a more practical level, the long-lasting, beneficial response to intermittent systemic hypoxia that we documented may be akin to the cross-organ benefits achieved by regular, intermittent exercise. In fact, both preclinical and clinical studies have consistently shown favorable effects of regular exercise "preconditioning" on stroke outcome. Moreover, a number of animal stroke studies implicate erythropoietin, the endogenous hormone that drives red cell production, as mediating the protective effects of preconditioning by hypoxia, hyperoxia, and other stimuli; although a recently concluded clinical trial was unable to demonstrate efficacy for treating patients with supplemental erythropoietin after they presented with stroke, an erythropoietin-based preconditioning treatment regimen may still be beneficial for those individuals at high risk for initial or recurrent stroke. While it is important to distinguish between stroke prophylaxis and stroke preconditioning (ie, the former reducing the incidence of stroke and the latter reducing the extent of injury in the event of stroke), we may ultimately learn that some treatments or interventions actually provide both. Even a cursory explanation of the genetic and molecular responses that could account for such effects is beyond the scope of this short perspective, but suffice it to say that the use of statins, and perhaps some dietary modifications, may very well represent examples of such phenotypic modulation.