Developmental neurotoxicity of general anesthesia: underlying mechanisms, prevention, and treatment

Abstract

Background More and more animal studies have demonstrated that general anesthesia can cause apoptosis in developing neurons. Epidemiological studies also demonstrate that long time or repetitive general anesthesia significantly increases the risk of postoperative cognitive dysfunction in young children less than 3 years old. However, the mechanisms of general anesthesia-induced developmental neurotoxicity is still unclear, meanwhile, no effective strategy for prevention and treatment has been found. Objective To explore the potential strategies for prevention and treatment by reviewing the mechanisms underlying developmental neurotoxicity of general anesthetics. Content General anesthetics modulate a variety of molecules in developing neurons and initiate or exacerbate apoptosis. First, as developing neurons contain high concentrations of Cl-, enhancement of γ-aminobutyric acid (GABA) A receptors by general anesthetics strengthens efflux of Cl- upon GABA stimulation, and subsequently leads to excitotoxicity of neurons. Second, upregulation of calcium-permeable N-methyl-D-aspanate(NMDA) receptors by ketamine may result in calcium overload. Third, general anesthetics inhibit the transformation of brain derived neurotrophic factor(BDNF) from prototype to mature one, which may induce apoptosis through p75 neurotrophin receptor(P75NTR) pathway. Fourth, some general anesthetics also cause accumulation of reactive oxygen species(ROS). Together with calcium overload, ROS induces mitochondrial malfunction. The neuronal apoptosis after general anesthesia can be followed by dysfunction of neural network and confer cognitive deficits. Accumulating studies found that targeting related ion channels, controlling calcium overload, reducing ROS production, and attenuating apoptosis can effectively protect neurons from degeneration following general anesthesia. Trend General anesthesia can cause apoptosis in developing neurons by targeting a variety of molecules, and these molecules or processes involving these molecules can be potential targets to prevent and treat general anesthesia-induced malfunctions. Key words: Neurotoxicity; Anesthesia general; Development; Apoptosis; Prevention and treatment