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

Abstract

Background: 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.Methods: 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.Results: 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.Conclusions: Preconditioning with xenon and sevoflurane provided long-lasting neuroprotection in a perinatal hypoxicischemic model and may represent a viable method to preempt neuronal injury after an unpredictable asphyxial event in the perinatal period.

Cooling Combined with Immediate or Delayed Xenon Inhalation Provides Equivalent Long-Term Neuroprotection after Neonatal Hypoxia—Ischemia

“…Xenon appears to induce a prosurvival response in cells that lasts longer than the period of Xe delivery, and it has been demonstrated that protein synthesis is a necessary step for this protection to occur, as protein synthesis blockade can inhibit these effects (Ma et al, 2006). Some suggested preconditioning mechanisms include increased gene transcription of activity-dependent neuroprotective protein (Cattano et al, 2008), enhanced phosphorylated cyclic adenosine monophosphate response element-binding protein signaling (Luo et al, 2008), and induction of hypoxiainducible factor-1a, which is known to promote expression of several prosurvival genes. Gene induction may emerge as an important mechanism for Xe neuroprotection (Garry et al, 2004); so it is possible that a long duration of Xe exposure may not be necessary.…”

Protein-Noble Gas Interactions Investigated by Crystallography on Three Enzymes - Implication on Anesthesia and Neuroprotection Mechanisms

“…When administrated after the reperfusion, xenon has beneficial effect by suppressing ischemic brain damage and tPA-induced brain hemorrhages Protein-Noble Gas Interactions Investigated by Crystallography on Three Enzymes -Implication on Anesthesia and Neuroprotection Mechanisms 287 (David et al, 2010) while nitrous oxide reduces ischemic brain damage but increases tPAinduced brain hemorrages (Haelewyn et al, 2011). Xenon is thus a very promising neuroprotective drug with few or no adverse side effects in models of acute ischemic stroke or perinatal hypoxia-ischemia (Homi et al, 2003;Ma et al, 2003;Abraini et al, 2005;David et al, 2008;Luo et al, 2008). Despite this, the widespread clinical use of xenon is limited by its scarceness and excessive cost of production, even if close xenon delivery systems are now being developed.…”

Como Funciona o Xénon: Mecanismos de Neuro e Cardioprotecção

“…Demonstrou-se, em modelos de asfixia neonatal em ratos, que a região de isquemia foi reduzida por pré-condicionamento com xénon a 75%, assim como as disfunções neurológicas a longo termo. 49 O seu uso em associação com a hipotermia, após um episó-dio de hipoxia neonatal, demonstrou ter efeitos sinérgicos na atenuação da lesão neuronal, 50 assim como o seu uso em associação com o isoflurano, um agonista GABA A , que também possui propriedades neuroprotectoras.…”