Inhibition of Rac1 attenuated propofol-induced neurotoxicity in the hippocampal dentate gyrus in developing mice

Accumulating evidence from animals has shown that multiple exposures to general anesthetics during brain development may cause extensive neuronal apoptosis and long-term memory impairments. However, the underlying mechanism is still poorly understood. In the present study, C57BL/6 mice were administered propofol at postnatal days 19–21. We found that propofol exposure significantly increased neuronal apoptosis in the mouse hippocampal dentate gyrus, as evidenced by cleaved caspase-3 (c-c3) immunofluorescence. Additionally, propofol exposure increased the activation and expression of Ras-related C3 botulinum toxin substrate 1 (Rac1) in the dentate gyrus, as shown by western blotting. Modulating Rac1, either through inhibition or overexpression, was found to mitigate or exacerbate propofol-induced neuronal apoptosis, respectively. We further demonstrated that propofol decreased the expression of the antiapoptotic protein phosphorylated serine/threonine kinase Akt via Rac1. The results of the open field and morris water maze tests further revealed that silencing Rac1 alleviated propofol-induced cognitive dysfunction. Our findings demonstrated that propofol exposure induced neuronal apoptosis and long-term cognitive dysfunction in the mouse hippocampal dentate gyrus by regulating Rac1.