Q&A with Mr. Koronowski
Stroke Progress and Innovation Awards 2015
Kevin B. Koronowski, BS
Kevin B. Koronowski, Kunjan R. Dave, Isabel Saul, Vladimir Camarena, John W. Thompson, Jake T. Neumann, Juan I. Young, and Miguel A. Perez-Pinzon
SPOTLIGHT: Q&A with Kevin Koronowski
What is the key take-away message from your article?
The take-home message of our study is that we uncovered a novel window of ischemic tolerance. We found that a single intraperitoneal injection of resveratrol, a naturally occurring polyphenol compound, 2 weeks prior to ischemia (resveratrol preconditioning) induces long-lasting mechanisms of neuroprotection. These findings strengthen the preclinical evidence supporting resveratrol as a treatment for cerebral ischemia and will provide other potential, robust targets for the future.
What prompted you and your co-authors to perform this study?
In our previous work, we found that resveratrol preconditioning protected rats against global cerebral ischemia as well as protected mice against focal ischemia if administered 2 days prior to the injury. In order to translate this potential treatment for stroke, we designed a study where we tested whether chronic administration of resveratrol, not unlike a clinical treatment regimen, could afford the same level of neuroprotection. Our initial results revealed molecular mechanisms which suggested that a longer time window of protection exists. Hence we designed new experiments that ultimately uncovered this new extended window of protection that lasts 2 weeks after a single administration of resveratrol.
What is innovative about this work? And what are its applications?
In the process of determining the most robust chronic treatment, we found that the neuroprotective effects of resveratrol lasted much, much longer than previously thought. Typically preconditioning paradigms are characterized by an early window of protection that takes shape within hours of the stimulus and a late window that becomes apparent within 2-3 days. Here, we discovered that there is actually an extended window of protection, which lasts at least 2 weeks following resveratrol preconditioning. It’s remarkable that one application of resveratrol could have such a pronounced and long-lasting effect on neuroprotection 2 weeks later. We went on to find that perhaps reprogramming events involving the epigenetic, metabolic regulator Sirt1 and downstream neuroprotective mediators could be at play in this extended window. We believe that characterization of the extended window will shed light on long lasting mechanisms of ischemic tolerance and provide drug-able targets with great potential as prophylactic treatments for cerebral ischemia and other ischemic events.
Tell us about the biggest challenge you came across while conducting this study.
Initially, we wanted to test the idea that ischemic tolerance could be “learned” over time with repetitive exposure to a stimulus (resveratrol), just as our recollection of memories strengthens when we are presented with that information intermittently through some period of time. This idea stemmed from the fact that there is now a very strong molecular basis for learning and memory in the brain and that our previous preconditioning studies suggest activation of similar signaling pathways (involved in synaptic plasticity) also occurs in our preconditioning paradigms. Thus, we surmised that perhaps intermittent exposure to resveratrol over time could “teach” the brain to resist ischemic injury. We were very excited when we indeed found that intermittent resveratrol preconditioning seemed to sustain ischemia tolerance well after the final exposure of resveratrol. However, when designing the control experiment for this paradigm, we did not think it would be possible to have a robust state of ischemic tolerance that lasted such a long time from just a single exposure of resveratrol. Much to our surprise, that is exactly what we found. These studies attempting to figure out how this extended window occurs and its molecular basis have been quite elaborate and prolonged given the complexity of preconditioning pathways. Teasing apart these mechanisms continues to be a major challenge within our ongoing research as we attempt to unravel this story.
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