Neonatal exposure to propofol induces persistent behavioral abnormalities in adulthood. In addition to triggering the apoptosis of neurons in the developing brain, anesthetics may contribute to the development of cognitive deficits by interfering neurogenesis. Given the importance of neural stem cell (NSC) proliferation in neurogenesis, the effect of propofol on NSC proliferation and the mechanisms underlying this effect were investigated. Hippocampal NSC proliferation from neonatal rats was examined using 5-bromo-2'-deoxyuridine incorporation assays in vitro. The [Ca2+]i was analyzed using flow cytometry. The activations of protein kinase C (PKC)-α and extracellular signal-regulated kinases 1/2 (ERK1/2) were measured by western blot. Our results showed that propofol significantly inhibited NSC proliferation in vitro. [Ca2+]i and activations of PKCα and ERK1/2 in NSCs were markedly suppressed by propofol (5, 10, 20, 40 and 80 μM). Ca2+ channel blocker verapamil, PKCα inhibitor chelerythrine and ERK1/2 kinase inhibitor PD98059 exerted their maximal effects on NSC function at concentrations of 20, 10 and 20 μM, respectively. Propofol (20 μM) could not produce further additional suppression effects when used in combination with verapamil (20 μM), chelerythrine (10 μM) or PD98059 (20 μM). In addition, phorbol-12-myristate-13-acetate (PMA, a activator of PKC) markedly attenuated the suppressive effects of propofol on ERK1/2 phosphorylation and NSC proliferation. The inhibition effects on PKCα activation, ERK1/2 phosphorylation and NSC proliferation induced by propofol were significantly improved by BayK8644 (a calcium channel agonist). These results indicate that propofol can inhibits hippocampal NSC proliferation by suppressing the Ca2+-PKCα-ERK1/2 signaling pathway.
Keywords: Calcium; ERK1/2; Hippocampus; Neural stem cell; PKC; Propofol.
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