Xenon and Sevoflurane Protect against Brain Injury in a Neonatal Asphyxia Model

Department of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
Anesthesiology (Impact Factor: 5.88). 12/2008; 109(5):782-9. DOI: 10.1097/ALN.0b013e3181895f88
Source: PubMed


Perinatal hypoxia-ischemia causes significant morbidity and mortality. Xenon and sevoflurane may be used as inhalational analgesics for labor. Therefore, the authors investigated the potential application of these agents independently and in combination to attenuate perinatal injury.
Oxygen-glucose deprivation injury was induced in pure neuronal or neuronal-glial cocultures 24 h after preconditioning with xenon and/or sevoflurane. Cell death was assessed by lactate dehydrogenase release or staining with annexin V-propidium iodide. The mediating role of phosphoinositide-3-kinase signaling in putative protection was assessed using wortmannin, its cognate antagonist. In separate in vivo experiments, perinatal asphyxia was induced 4 hours after preconditioning with analgesic doses alone and in combination; infarct size was assessed 7 days later, and neuromotor function was evaluated at 30 days in separate cohorts. The role of phosphorylated cyclic adenosine monophosphate response element binding protein in the preconditioning was assessed by immunoblotting.
Both anesthetics preconditioned against oxygen-glucose deprivation in vitro alone and in combination. The combination increased cellular viability via phosphoinositide-3- kinase signaling. In in vivo studies, xenon (75%) and sevoflurane (1.5%) alone as well as in combination (20% xenon and 0.75% sevoflurane) reduced infarct size in a model of neonatal asphyxia. Preconditioning with xenon and the combination of xenon and sevoflurane resulted in long-term functional neuroprotection associated with enhanced phosphorylated cyclic adenosine monophosphate response element binding protein signaling.
Preconditioning with xenon and sevoflurane provided long-lasting neuroprotection in a perinatal hypoxic-ischemic model and may represent a viable method to preempt neuronal injury after an unpredictable asphyxial event in the perinatal period.

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Available from: Daqing Ma, Jan 13, 2014
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    • "Moreover, we also found that rats that underwent a 6-hour treatment with 1.8% sevoflurane performed better in the acquisition stage of the Morris water maze test and in the contextual discrimination fear learning test, tasks that have been shown to be affected by hippocampal neurogenesis (Kee et al., 2007; Sahay et al., 2011; Nakashiba et al., 2012). Our findings are consistent with previous reports which demonstrated that subanesthetic doses of sevoflurane provide neuroprotection in hypoxic-ischemic animal models (Luo et al., 2008; Chen et al., 2014; Ren et al., 2014). High concentrations of sevoflurane have also been reported to promote neurogenesis in the DG after cerebral ischemia (Engelhard et al., 2007), perhaps indicating that neurons in the ischemic brain respond differently to sevoflurane than in normal conditions. "
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    ABSTRACT: Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. © The Author(s) 2015.
    ASN Neuro 04/2015; 7(2). DOI:10.1177/1759091415575845 · 4.02 Impact Factor
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    • "Another beneficial property of Xenon is its non-toxic chemical characteristic which enables the usage of the gas on neonates. The high risk of any traumatic event during childbirth brings the idea of Xenon preconditioning to mother as a method of reducing the possibility of brain insult to the neonate [46]. Xenon is an ideal gas for this model with its cardiovascular stability [47] and myocardial protection property [48], as well as its rapid induction rate through blood–brain-barrier [14,49]. "
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    ABSTRACT: Xenon is a medical gas capable of establishing neuroprotection, inducing anesthesia as well as serving in modern laser technology and nuclear medicine as a contrast agent. In spite of its high cost, its lack of side effects, safe cardiovascular and organoprotective profile and effective neuroprotective role after hypoxic-ischemic injury (HI) favor its applications in clinics. Xenon performs its anesthetic and neuroprotective functions through binding to glycine site of glutamatergic N-methyl-D-aspartate (NMDA) receptor competitively and blocking it. This blockage inhibits the overstimulation of NMDA receptors, thus preventing their following downstream calcium accumulating cascades. Xenon is also used in combination therapies together with hypothermia or sevoflurane. The neuroprotective effects of xenon and hypothermia cooperate synergistically whether they are applied synchronously or asynchronously. Distinguishing properties of Xenon promise for innovations in medical gas field once further studies are fulfilled and Xenon's high cost is overcome.
    02/2013; 3(1):4. DOI:10.1186/2045-9912-3-4
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    • "This was true in the xenon preconditioning [24,32-34]. The late myocardial protective effect of xenon preconditioning was found to be closely related to the cyclooxygenase-2 (COX-2) activity because inhibition of COX-2 abolished this cardioprotective effect and the mRNA and protein expression of COX-2 remained unchanged following xenon preconditioning [32], the enhanced phosphorylated cyclic adenosine monophosphate response element binding protein signaling [33] and the phosphorylated cAMP-response element binding protein (pCREB)-regulated synthesis of proteins that promote survival against neuronal injury (Table 1) [33,34]. "
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    ABSTRACT: Xenon is one of noble gases and has been recognized as an anesthetic for more than 50 years. Xenon possesses many of the characteristics of an ideal anesthetic, but it is not widely applied in clinical practice mainly because of its high cost. In recent years, numerous studies have demonstrated that xenon as an anesthetic can exert neuroprotective and cardioprotective effects in different models. Moreover, xenon has been applied in the preconditioning, and the neuroprotective and cardioprotective effect of xenon preconditioning have been investigated in a lot of studies in which some mechanisms related to these protections are proposed. In this review, we summarized these mechanisms and the biological effects of xenon preconditioning.
    01/2013; 3(1):3. DOI:10.1186/2045-9912-3-3
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