Reprogramming the Response to Stroke by Preconditioning

Stroke causes neuronal injury and death because of deprivation of oxygen and nutrients that are essential for cell survival. In addition, inflammatory mediators are released that trigger a cascade of responses that exacerbate injury. Although these injurious pathways are well defined, it has been a major challenge to identify ways to mitigate these pathways to reduce ischemic damage. One approach to the management of stroke injury under development in the research laboratory involves tapping into powerful endogenous mechanisms of protection through a process known as preconditioning. Preconditioning is a well-defined phenomenon whereby a small dose of an otherwise-harmful stimulus confers tolerance to a subsequent injurious event. Preconditioning stimuli that provide significant protection against ischemic brain injury include exposure to brief ischemia, small seizures, immune activation, exposure to hypo- and hyperthermia, and inhalation of volatile anesthetics.1 Although distinct, these preconditioning stimuli initiate a cascade of endogenous neuroprotective pathways that produce tolerance to ischemic injury.2–7 Preconditioning with the immune activators Toll-like receptor (TLR) ligands has shown exceptional efficacy in the induction of ischemic tolerance. Systemic administration of ligands for TLR2, TLR4, TLR7, or TLR9 before focal cerebral ischemia profoundly reduces ischemic injury in rodent models of stroke.8–12 TLR preconditioning has also been shown to be effective in a neonatal ischemia model, demonstrating significant cerebral protection against hypothermic circulatory arrest in neonatal pigs.13 In addition, the TLR9 ligand has shown significant efficacy in a clinically relevant nonhuman primate model of experimental stroke.14 Many TLR ligands have been approved for clinical use in other indications,15 making them ideal candidates for translation of pharmacological preconditioning from the laboratory to the clinic. Preconditioning is being developed as a prophylactic treatment for cerebral ischemia and is being investigated at …