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Isoflurane preconditioning-induced neuroprotection

时间:2018-05-21 英语毕业论文 我要投稿

毕业论文


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 rious 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

1. Martin, J.A., et al., Births and Deaths: Preliminary Data for 1998. National Vital Statistics Reports, 1999. 47(25): p. 1-45.
2. Muir, K.W. and K.R. Lees, Clinical experience with excitatory amino acid antagonist drugs. Stroke, 1995. 26(3): p. 503-513.
3. Kataoka, K. and H. Yanase, Mild hypothermia--a revived countermeasure against ischemic neuronal damages. Neuroscience Research, 1998. 32(2): p. 103-17.
4. Tomai, F., et al., Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation, 1999. 100(5): p. 559-63.
5. Ferrari, R., et al., Ischemic preconditioning, myocardial stunning, and hibernation: basic aspects. American Heart Journal, 1999. 138(2 Pt 2): p. S61-8.
6. Nandagopal, K., T.M. Dawson, and V.L. Dawson, Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. The Journal of Pharmacology and Experimental Therapeutics, 2001. 297(2): p. 474-8.
7. Schulz, R.C., M.V.; Behrends, M.; Downey, J.M.; Heusch, G., Signal transduction of ischemic preconditioning. Cardiovascular Research, 2001. 52: p. 181-98.
8. Li, J., S. Zheng, and Z. Zuo, Isoflurane decreases AMPA-induced dark cell degeneration and edematous damage of Purkinje neurons in the rat cerebellar slices. Brain Research, 2002. 958(2): p. 399-404.
9. Zheng, S. and Z. Zuo, Isoflurane preconditioning reduces Purkinje cell death in an in vitro model of rat cerebellar ischemia. Neuroscience, 2003. 118(1): p. 99-106.
10. Wang, C., et al., Pretreatment with volatile anesthetics, but not with the nonimmobilizer 1,2-dichlorohexafluorocyclobutane, reduced cell injury in rat cerebellar slices after an in vitro simulated ischemia. Brain Research, 2007. In press.
11. Choi, D.W., Glutamate receptors and the induction of excitotoxic neuronal death. Progress in Brain Research, 1994. 100: p. 47-51.
12. Zheng, S. and Z. Zuo, Isoflurane preconditioning decreases glutamate receptor overactivation-induced Purkinje neuronal injury in rat cerebellar slices. Brain Res, 2005. 1054(2): p. 143-51.
13. Kapinya, K.J., et al., Tolerance Against Ischemic Neuronal Injury Can Be Induced by Volatile Anesthetics and Is Inducible NO Synthase Dependent. Stroke, 2002. 33: p. 1889-1898.
14. Zheng, S. and Z. Zuo, Isoflurane preconditioning induces neuroprotection against ischemia via activation of p38 mitogen-activated protein kinase. Molecular Pharmacology, 2004. 65: p. 1172-1180.
15. Zuo, Z., Y. Wang, and Y. Huang, Isoflurane preconditioning protects human neuroblastoma SH-SY5Y cells against in vitro simulated ischemia-reperfusion through the activation of extracellular signal-regulated kinases pathway. Eur J Pharmacol, 2006. 542(1-3): p. 84-91.
16. Zhao, P. and Z. Zuo, Isoflurane preconditioning induces neuroprotection that is inducible nitric oxide synthase-dependent in the neonatal rats. Anesthesiology, 2004. 101: p. 695-702.
17. Unpublished results.

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