Abstract
BackgroundErythropoietin (EPO), originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is also endogenously expressed in the central nervous system (CNS). EPO in the CNS, mainly produced in astrocytes, is induced under hypoxic conditions in a hypoxia-inducible factor (HIF)-dependent manner and plays a dominant role in neuroprotection and neurogenesis. We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes.Methodology/Principal FindingsBALB/c mice were exposed to 10% oxygen with isoflurane at various concentrations (0.10–1.0%). Expression of EPO mRNA in the brain was studied, and the effects of sevoflurane, halothane, nitrous oxide, pentobarbital, ketamine, and propofol were investigated. In addition, expression of HIF-2α protein was studied by immunoblotting. Hypoxia-induced EPO mRNA expression in the brain was significantly suppressed by isoflurane in a concentration-dependent manner. A similar effect was confirmed for all other general anesthetics. Hypoxia-inducible expression of HIF-2α protein was also significantly suppressed with isoflurane. In the experiments using primary cultured astrocytes, isoflurane, pentobarbital, and ketamine suppressed hypoxia-inducible expression of HIF-2α protein and EPO mRNA.Conclusions/SignificanceTaken together, our results indicate that general anesthetics suppress activation of HIF-2 and inhibit hypoxia-induced EPO upregulation in the mouse brain through a direct effect on astrocytes.
Highlights
Ischemic and hypoxic insults to the brain during surgery and anesthesia result in life-threatening complications including stroke
Effect of various anesthetics on oxygen consumption in primary cultured astrocytes To investigate the precise mechanism of how general anesthetics suppress the induction of EPO under hypoxic conditions, we examined the influence of general anesthetics on oxygen consumption in astrocytes
Various studies have focused on the function of EPO in central nervous system (CNS); for example, mice lacking EPO or EPO receptor (EPOR) exhibited increased apoptosis in the brain before they died from severe anemia in utero [39,40], and mice lacking EPOR in the brain suffered from reduced neurogenesis or impaired migration of neurons in a brain stroke model [41]
Summary
Ischemic and hypoxic insults to the brain during surgery and anesthesia result in life-threatening complications including stroke These complications occur at the rate of 0.08–0.7% in general surgery and 1.4–3.8% in cardiac surgery [1]. Further investigations expanded this review by showing that EPO and EPO receptor (EPOR) are present in the human brain and synthesized locally by astrocytes and neurons [6,7,8,9] It is well documented in both experimental and clinical studies that EPO produced in the brain acts in a paracrine or autocrine manner to provide neuroprotection [10,11]. Erythropoietin (EPO), originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is endogenously expressed in the central nervous system (CNS). We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes
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