Background Recent studies in various animal models have suggested that anesthetics
Background Recent studies in various animal models have suggested that anesthetics such as propofol, when administered early in life, can lead to neurotoxicity. and Activator of Transcription 3 (STAT3) and protein kinase B (Akt) were downregulated and Sprouty 2 was upregulated following propofol exposure (n = 3). Conclusions These data suggest that: (1) hESC-derived neurons represent a promising human model for studying anesthetic-induced neurotoxicity, (2) propofol inducecell death in hESC-derived neurons and (3) the propofol-induced cell death may occur via a STAT3/miR-21/Sprouty2-dependent mechanism. Introduction It is estimated that 4 million children PHA-793887 are administered anesthetic agents every year in the United States for imaging or surgical purposes.1 The deleterious effects of anesthetic exposure on the developing brain in animals have been well-established and several anesthetics, including propofol, have been shown to induce neuronal cell death in neonatal rat and primate models.2C5 Moreover, anesthetic exposure has been linked to learning disabilities and impaired cognitive function which has raised safety concerns regarding the use of anesthetics in children.6,7. However, the use of anesthetic agents in young children is often unavoidable. Therefore, it is critical to understand the effects of anesthetics on developing human neurons and their mechanisms of action in order to minimize any neurotoxic effects of these agents. The mechanisms involved in developmental anesthetic-induced neurotoxicity are not well understood and until recently, much of the research in the neurodegenerative field was performed in animal models with no direct evidence available in a human model. Additionally, for ethical reasons, it is PHA-793887 not feasible to perform these studies on young children and the only human data available comes from a limited number of epidemiological studies.8C11 Moreover, these human studies are often limited by many confounding variables and have produced widely mutable results. Therefore, the neurological effects of anesthetics PHA-793887 on young children remain uncertain. Human embryonic stem cells (hESCs) are pluripotent cells that are derived from the inner cell mass of a human blastocyst.12 The benefit of using hESCs lies in their ability to differentiate into any cell type making them a potentially powerful model of human physiology and pathophysiology. Therefore, neurons derived from hESCs are a valuable model Mouse monoclonal to KSHV ORF45 to directly study the effects of anesthetics on immature, human-derived neurons. MicroRNAs (miRs) are endogenous, non-coding RNA molecules that act to regulate nearly every cellular process through inhibition of target messenger RNA expression. MicroRNAs are produced through the processing of long stem-loop transcripts by the nucleases Drosha and Dicer. The mature microRNA then combines with the RNA-induced silencing complex (RISC) and interacts with its target to induce gene silencing through target mRNA degradation or translational repression.13 MicroRNAs have been implicated to play important roles in many different disease processes, including neurological diseases.14C16 Neurotoxicity conferred by ethanol, cocaine, Huntingtons disease, and brain injuries have all been linked to microRNA dysregulation.17 However, the role of microRNAs in anesthetic-induced neurotoxicity has yet to be studied. One microRNA, miR-21, has been shown to decrease apoptosis and can protect neurons from ischemic injury. Exposure of fetal cerebral cortical-derived neuroepithelial cells to ethanol was shown to suppress miR-21.18 miR-21 has been shown to decrease apoptosis in varying cell types by directly targeting and suppressing Sprouty 2 which, in turn, negatively regulates Protein Kinase B (Akt) activation.19C23 Additionally, Signal Transducer and Activator of Transcription 3 (STAT3) is a known regulator of miR-21.24C28 After screening microRNAs and finding that miR-21 was downregulated following exposure to propofol, we hypothesized that the miR-21 signaling pathway (STAT3/Sprouty2/Akt).