Astrocytes and ischemic tolerance

A mild non-lethal ischemic episode can induce resistance to a subsequent severe ischemic injury in the brain. This phenomenon is termed ischemic tolerance or ischemic preconditioning, and is an endogenous mechanism that can provide robust neuroprotection. Because of its neuroprotective effects against cerebral ischemia or stroke, ischemic tolerance has been widely studied. However, almost all studies have been performed from the viewpoint of neurons. Accumulating evidence suggests that glial cells have various roles in regulation of brain function, including modulation of synaptic transmission, neuronal excitation, and neuronal structure. In addition, astrocytes are closely related to homeostasis, stability of brain function, and protection of neurons. However, glial cells have received only limited attention with regard to ischemic tolerance. Cross-ischemic preconditioning is a phenomenon whereby non-ischemic preconditioning such as mechanical, thermal, and chemical treatment can induce ischemic tolerance. Of these, chemical treatments that affect the immune system can strongly induce ischemic tolerance, suggesting that glial cells may have important roles in this process. Indeed, we and others have demonstrated that glial cells, especially astrocytes, play a pivotal role in the induction of ischemic tolerance. This glial-mediated ischemic tolerance provides a robust and long-lasting neuroprotection against ischemic injury. In this review, we discuss the mechanisms underlying glial-mediated ischemic tolerance, as well as its potential benefits, problems, and therapeutic application.