Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top 10 killers in the USA [1]. Many interventions, such as induction of hypothermia and use of glutamate receptor antagonists, have been explored for potential neuroprotection against ischemia [2, 3]. However, clinically practical methods to reduce ischemic brain injury have not been well established yet.
Ischemic preconditioning is a well known phenomenon in which brief episodes of sub-lethal ischemia induce a robust protection against the deleterious effects of subsequent, prolonged, lethal ischemia in many organs, including brain and heart [4, 5]. Early studies showed that cardiac ischemic preconditioning occurred in two temporal phases: acute and delayed [6, 7]. The acute phase is mediated by function changes of existing proteins, is present within minutes, and disappears 2-3 hours later [6]. The delayed phase develops hours after the preconditioning event, requires new protein synthesis, and is sustained for several days [6, 7].
We showed for the first time that preconditioning with the volatile anesthetic isoflurane induced an acute phase of neuroprotection [8]. Our subsequent study showed that this isoflurane preconditioning-induced acute phase of neuroprotection was dose-dependent with an EC50 1.17% and that preconditioning the brain with isoflurane for 15-30 min was needed for the preconditioning to be maximally protective. This effect was glutamate transporter-dependent [9]. Other volatile anesthetics, such as sevoflurane, halothane and desflurane, also induced preconditioning effects in the brain. The potency of this protection induced by volatile anesthetics is correlated with their potencies of inducing immobility [10]. Since glutamate accumulation and the subsequent glutamate receptor over-stimulation play a critical role in the ischemic brain injury [11], we determined whether isoflurane preconditioning reduced glutamate receptor over-stimulation-induced neuronal death. Our results showed that isoflurane preconditioning reduced the neuronal death caused by over-stimulation of the major glutamate receptors [12].
Kapinya et al should be credited as the first group to show that isoflurane preconditioning induced a delayed phase of neuroprotection [13]. Our in vivo study showed that this protection was mediated by the activation of the mitogen-activated protein kinase p38 [14]. The isoflurane preconditioning-induced protection in human neuroblastoma SH-SY5Y cells involved the extracellular signal-regulated kinase-early growth response gene 1-Bcl-2 pathway activation [15]. Our in vivo study also showed that isoflurane preconditioning induced a delayed phase of protection in immature brains [16]. This protection was sustained even when animals were examined at one month after the brain ischemia [17].
In summary, volatile anesthetics can induce acute and delayed phases of preconditioning effects in the brain. Since isoflurane is a relatively safe agent and has been frequently used in patients with potential brain ischemia, these patients may have already benefited from its preconditioning effects. Studying the mechanisms of volatile anesthetic preconditioning-induced neuroprotection may identify new targets/interventions for ischemic brain injury.
References

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17. Unpublished results.