Sevoflurane Inhibits the Proliferation of Neural Precursor Cells and Neural Migration of Mice by Inducing Iron Metabolism Disorders

Abstract

Background: Sevoflurane (Sev) is a volatile anesthetic and inhibits the proliferation of neural precursor cells (NPCs) and neuronal migration in the embryonic brain, thereby affecting offspring's cortical development and cognitive function.

Methods: Pregnant mice were treated with 2.5% Sev. In utero, plasmids with GFP were electroporated into embryonic cortical neural precursor cells. Cell proliferation and neurite growth were detected by immunofluorescence of Ki67, pH 3, BrdU, Map2, and phalloidin labeling, respectively. Ferritin, transferrin receptor1 (TfR1), and confilin were detected by western blot.

Results: Sev inhibited the proliferation of NPCs by down-regulating the expression of pH 3 and Ki67, and also delayed the radial migration of cortical neurons. Sev impaired the multipolar-to-bipolar transition of migrating neurons by affecting Golgi orientation. Furthermore, Sev down-regulated the expression of TfR1and increased the protein levels of ferritin heavy chain (FtH) and ferritin light chain (FtL) and caused the iron accumulation in the brain. Meanwhile, Sev induced the abnormal depolymerization and polymerization of microfilaments by increasing the ratio of p-Cofilin/Cofilin and decreasing the ratio of F-actin/G-actin. Meanwhile, Sev inhibited cortical development by decreasing the neurite growth and number of branches of neurites. DFO, an iron-chelating agent, could significantly ameliorate the inhibitory effect of Sev on the proliferation of NPCs and radial migration of projection neurons.

Conclusions: Sev inhibited the NPCs proliferation and neuronal migration by inducing iron metabolic dysfunction. Regulating iron homeostasis could protect the cortical development of the embryo against Sev exposure during pregnancy.

Keywords: cell proliferation; cortical development; iron metabolism; neuronal migration; sevoflurane.