Administration of Ketamine Causes Autophagy and Apoptosis in the Rat Fetal Hippocampus and in PC12 Cells

Abstract

Drug abuse during pregnancy is a serious problem. Like alcohol, anticonvulsants, sedatives, and anesthetics, such as ketamine, can pass through the placental barrier and affect the growing fetus. However, the mechanism by which ketamine causes damage to fetal rats is not well understood. Therefore, in this study, we anesthetized pregnant rats with ketamine and evaluated the Total Antioxidant Capacity (T-AOC), Reactive Oxygen Species (ROS), and Malondialdehyde (MDA). Moreover, we determined changes in the levels of Cleaved-Caspase-3 (C-Caspase-3), Beclin-1, B-cell lymphoma-2 (Bcl-2), Bcl-2 Associated X Protein (Bax), Autophagy-related gene 4 (Atg4), Atg5, p62 (SQSTM1), and marker of autophagy Light Chain 3 (LC3). In addition, we cultured PC12 cells in vitro to determine the relationship between ROS, autophagy, and apoptosis following ketamine treatment. The results showed that ketamine induced changes in autophagy- and apoptosis-related proteins, reduced T-AOC, and generated excessive levels of ROS and MDA. In vitro experiments showed similar results, indicating that apoptosis levels can be inhibited by 3-MA. We also found that autophagy and apoptosis can be inhibited by N-acetyl-L-cysteine (Nac). Thus, anesthesia with ketamine in pregnant rats may increase the rate of autophagy and apoptosis in the fetal hippocampus and the mechanism may be through inhibition of antioxidant activity and ROS accumulation.

Clozapine protects adult neural stem cells from ketamine-induced cell death in correlation with decreased apoptosis and autophagy

“…Our results showed that the anti-apoptotic activity of clozapine was associated with attenuated autophagy evident by decreased protein levels of LC3-II. The result was in accordance with previous studies where agents that attenuated ketamine neurotoxicity were associated with decreased apoptosis and autophagy [66,67]. These data suggest that clozapine may inhibit the accumulation of toxic protein aggregates and defective organelles that ketamine introduces to the cells, causing an accumulation of dysfunctional autophagosomes.…”

“…We and others have previously shown that ketamine causes apoptosis [24,66] and up-regulates autophagy [67]. To explore the underlying mechanism of observed NSC protection and anti-apoptotic activity, induced by clozapine, we investigated the effect of clozapine on autophagy.…”

Alterations in the autonomic nerve activities of prenatal autism model mice treated with valproic acid at different developmental stages

“…In postnatal experiments, mice were anesthetized with isoflurane. It was reported that ketamine passes through the placental barrier and affects the fetus 58,59 . Ketamine/xylazine affect HR 60 , which is reduced by isoflurane in mice 61 .…”

Impaired lipophagy in endothelial cells with prolonged exposure to oxidized low‑density lipoprotein

“…Autophagy is a process of evolutionarily conserved catabolism, which degrades a number of cellular components, including long-lived proteins and various organelle components ( 12 , 13 ). A high LC3-II to LC3-I ratio reflects increasing autophagosome formation, whereas low p62 protein levels are associated with high autophagy flux ( 14 , 15 ). LAMP1 is an essential component of the lysosomal membrane, serving as a lysosomal biomarker with a key role in autophagy and lysosomal fusion ( 16 ).…”