preconditioning-induced

Anesthesia basic science research
Isoflurane preconditioning-induced neuroprotection
Zhiyi Zuo
University of Virginia, Charlottesville, VA 22908, USA
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 （转载自科教范文网http://fw.nseac.com）
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
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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.