Preconditioning paradigms and pathways in the brain
ABSTRACT
Preconditioning is a phenomenon in which the brain protects itself against future injury by adapting to low doses of noxious insults. Preconditioning stimuli include ischemia, low doses of endotoxin, hypoxia, hypothermia and hyperthermia, cortical spreading depression, anesthetics, and 3-nitropropionic acid, among others. Understanding of the mechanisms underlying preconditioning has been elusive, but NMDA receptor activation, nitric oxide, inflammatory cytokines, and suppression of the innate immune system appear to have a role. Elucidation of the endogenous cell survival pathways involved in preconditioning has significant clinical implications for preventing neuronal damage in susceptible patients.
Role of microglia in ischemic preconditioning
Microglia represent the resident central nervous system (CNS) component of the innate immune system. Microglia and macrophages become activated with ischemia in the infarcted and surrounded area.88 Upon activation in ischemia, microglia will become phagocytic and secrete a multitude of noxious chemokines and cytokines.89 Accordingly, anti-inflammatory antibiotics such as doxycycline and minocycline reduce microglial activation and diminish the ischemic infarction area.90 Preconditioning the brain with LPS ameliorates microglial activation, neutrophil infiltration, and circulating monocyte activation following MCAO.35 However, primary ischemic damage is not correlated with CNS infiltration of peripheral leukocytes but rather with an increase in proliferating resident microglial cells.91 Alternatively, microglia can exhibit neuroprotective properties within the brain.92 In fact, greater ischemic damage from longer periods of MCAO is correlated with fewer proliferating microglia, suggesting a protective microglial role.91 Consistently, ablation of proliferating microglia increases the infarction area following MCAO.93 Therefore, microglia can be protective in ischemia, and preconditioning with LPS may render microglia more capable of reacting to ischemic conditions.
CONCLUSIONS
Preconditioning represents an adaptive response to prime the brain for protection against future injury. Elucidation of these endogenous cell survival pathways has significant clinical implications for preventing neuronal damage in susceptible patients. For this reason, understanding the underlying mechanisms in establishing a tolerant state will be a critical step in adapting preconditioning for safe patient applications. The field of ischemic research has made great strides in deciphering causative preconditioning factors but has been hampered by the complex, multifactorial nature of preconditioning paradigms. The study of tolerance is further complicated by the fact that signaling takes place both peripheral to and within the brain in multiple cell types. Future research will require the exploration of interactions between multiple pathways and roles of individual cell types in establishing ischemic tolerance. Only with a more thorough understanding of preconditioning mechanisms can we adapt these pathways for the most efficient and protective treatments.
