Biological networks in ischemic tolerance - rethinking the approach to clinical conditioning

Abstract

The adaptive response (conditioning) to environmental stressors evokes evolutionarily conserved programs in uni- and multicellular organisms that result in increased fitness and resistance to stressor induced injury. Although the concept of conditioning has been around for a while, its translation into clinical therapies targeting neurovascular diseases has only recently begun. The slow pace of clinical adoption might be partially explained by our poor understanding of underpinning mechanisms and of the complex responses of the organism to the stressor. At the 2(nd) Translational Preconditioning Meeting participants engaged in an intense discussion addressing whether the time has come to more aggressively implement clinical conditioning protocols in the treatment of cerebrovascular diseases or whether it would be better to wait until preclinical data would help to minimize clinical empiricism. This review addresses the complex involvement of biological networks in establishing ischemic tolerance at the organism level using two clinically promising conditioning modalities, namely remote ischemic preconditioning, and per- or post-conditioning, as examples.

Figure 1. System networks in remote ischemic preconditioning

Trigger ischemia in the remote tissue (upper arm) induces the generation and/or release of triggers and mediators that act locally by activating sensory neurons that signal to CNS centers. Alternatively, they may function as humoral factors directly on the target organ (brain) to induce ischemic tolerance or by regulating other organ systems involved in ischemic tolerance (vasculature, immune system). Afferent neural signals are integrated and evoke the activation of efferent neurohumoral pathways that could directly alter the response of the brain tissue to index ischemia or evoke systemic effects on the vasculature (increased NO production) and the immune system (immunomodulating and down-regulating its activity) that feed back to the ischemic brain and participate in the neuroprotective response. The response is characterized by improved neurovascular function, resistance to excitotoxicity and proapoptotic signals, reduced post-ischemic inflammation, and increased production of trophic factors involved in tissue repair.