Preconditioning the brain: moving on to the next frontier of neurotherapeutics.

In December 2011, the 2 nd Translational Preconditioning Meeting was held at the University of Miami Miller School of Medicine. The motivation for this meeting arose from the success of the first meeting organized by Dr Guohua Xi and Dr Richard Keep at the University of Michigan, which took place in Ann Arbor in 2009. The main goal of the Miami meeting was to discuss and identify effective strategies to promote the basic science research of ischemic preconditioning for neurological diseases, with the ultimate objective of advancing ischemic preconditioning therapies to clinical use. With this goal in mind, the meeting was divided into clinical and basic science sessions. The discussions were organized in a question-and-answer format. More than 40 national leaders in the field attended the meeting to exchange ideas and brainstorm on ways to translate the basic science of preconditioning to clinical neurology (for a list of attendees and meeting agenda, please see online-only Supplemental Materials). The meeting took place over only 1 day and, given the early stages of development of this workshop, it was felt prudent to limit attendance to United States nationals. The organizers acknowledged this as a shortcoming of the conference that will, hopefully, be remedied in the future as the scope of the meeting expands. The purpose of this editorial is to summarize the key elements that arose out of these discussions in response to several questions posed to the attendants. The preconditioning phenomenon rests on the basic premise that organisms have developed complex and active defenses to counter adversarial conditions such as starvation and oxygen deprivation.1,2 From an evolutionary point of view, successful adaptation to environmental stress ensured survival. Triggering these innate defense systems to maintain cellular homeostasis, in the face of noxious injury, is at the root of the preconditioning response, which rests on the central principle that mild forms of stress induce tolerance to an otherwise lethal injury. Thus, it has been shown that preconditioning the brain with brief occlusions of a cerebral artery leads to a reduction in infarct size in laboratory models of stroke or cardiac arrest.3–6 Many stimuli, such as ischemia, pharmacological agents, hypoxia, hypothermia, and essentially anything that causes cellular stress, induce a preconditioning response.7 In laboratory models of ischemia, consistent protection from noxious durations of ischemia has been demonstrated in many different organs. Whereas preconditioning is one of the most powerful laboratory anti-ischemic strategies known, its clinical potential has remained unexplored in neurological disorders. Several clinical studies have been completed in cardiac medicine and, for the most part, have shown a diminution of surrogate markers of myocardial ischemia.8 Only few such studies have been reported concerning neurological conditions, and many questions remain regarding the most favorable clinical setting to test the preconditioning phenomenon, the optimal preconditioning stimulus, and whether a cerebral preconditioning response can even be induced in humans who, in contrast to laboratory animals, are elderly and have multiple comorbidities.9–11 A recent PubMed search lists 1160 entries for ischemic preconditioning and brain alone, showing a trend of logarithmic increase in publications in this field over the past few years (1986–2012). Such an abundance of largely preclinical data naturally begets the question of whether the concept of preconditioning is ready to be incorporated into clinical trials. The general sentiment of the attendees was to proceed with clinical studies, prudently. A few preliminary trials already have been completed in neurological disorders and others were in progress. Many preconditioning trials have been performed in cardiac medicine, even though the optimal preconditioning stimulus for myocardial protection also remains poorly characterized. Although all agreed that the past failures of translating neuroprotection to clinical medicine needed to be avoided, applying STAIR-like criteria12 to preconditioning agents or techniques was controversial and not fully endorsed. It was clear from the discussion that STAIR-like criteria should be tailored specifically to preconditioning and should be different from those developed for neuroprotection, because this phenomenon is clearly distinct from poststroke treatment. There was a general understanding that such trials needed to be conducted cautiously and needed to be exploratory, with an emphasis on finding suitable biomarkers to measure whether a preconditioning response is even able to be elicited in humans. There was concern that the stress of concomitant disease, advanced age, and widespread medication use in human subjects might modify and even prevent preconditioning. The search for a suitable biomarker also could be the objective of additional laboratory investigations of precondiReceived January 24, 2012; accepted February 15, 2012. The opinions in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL. The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/ STROKEAHA.111.646919/-/DC1. Correspondence to Miguel A. Perez-Pinzon, PhD, Department of Neurology, D4-5, University of Miami Miller School of Medicine, PO Box 016960, Miami, FL 33101. E-mail [email protected] (Stroke. 2012;43:1455-1457.) © 2012 American Heart Association, Inc.