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    • At present the role of autophagy in neurons

    2024-03-27

    At present, the role of autophagy in neurons remains controversial. Autophagy has homeostatic and waste-recycling functions and plays a protective role in neurodegeneration diseases. Moreover, it has been thought as a programmed cell death participating in the occurrence and development of various diseases (Button et al., 2015). Our results showed that autophagic vacuoles (autophagosomes) comprised of membranous structures or cellular material elevated in hippocampal neurons Bezafibrate after 3.4% sevoflurane plus 60% oxygen for 4 h × 3d exposure by transmission electron microscopy, which confirmed the results of Sanchez et al. (2011). These suggested that the immature neurons autophagic load may be promoted by general anesthesia and autophagy has an essential influence on neurons cell survival. subsequent maturation and autophagosomes degradation (Matus et al., 2014). A marker protein on the membranes of autophagosomes is light chain 3 of microtubule-associated protein 1 (MAP1-LC3). LC3- I can be coupled with phosphatidylethanolamine to form LC3-II after the formation of autophagosome. To some extent, LC3-II reflects the number of autophagosomes (Klionsky et al., 2016). Beclin-1/BECN1, a component of the phosphatidylinositol-3-kinase (PI3K) complex, correlated with the formation of autophagosome and the regulation of autophagy and apoptosis. It is important in the programmed cell death process (Klionsky et al., 2016). P62/SQSTM1, as a regulating factor involved in the autophagosome composition, is degraded during autophagy middle-late stage. The change of P62/SQSTM1 expression can be used to monitor autophagy and is negatively correlated with the activity of autophagy (Klionsky et al., 2016). Chen et al. (2012) showed that ethanol elevated the Map1lc3-II (LC3-II) level and increased SH-SY5Y neuroblastoma cells LC3 puncta. Furthermore, ethanol increased LC3-II and BECN1 levels and reduced SQSTM1 (p62) levels in the puberty brain. In our study, Beclin-1 and LC3-II protein levels dramatically elevated while P62 protein levels markedly decreased after exposure to 3.4% sevoflurane for 4 h × 3d in rat hippocampus, suggesting that sevoflurane enhances the development of autophagosomes but not blocks the fusion of lysosomes and autophagosomes. Moreover, we showed that the levels of Beclin-1mRNA, LC3mRNA as well as the number of LC3-positive and Beclin-1-positive neuron increased, while the levels of P62 mRNA decreased after sevoflurane exposure. This provided strong support that sevoflurane may improve autophagic maturation and initiation and also accelerate autophagic flux in hippocampus neurons. The mammalian target of rapamycin (mTOR) pathway is vital during cell growth and autophagy procedure (Liu et al., 2016). Rapamycin is an inhibitor of mTOR and an activator of autophagy. The autophagosomes formation and the Class III PI3K were inhibited by 3-methyladenine (Ma et al., 2015). Our study showed that the level of Beclin-1and LC3-II protein significantly increased after intraperitoneal injection of rapamycin. But they significantly decreased after intraperitoneal injection of 3-MA, indicating that mTOR inhibition causes enhanced autophagy and inhibition of Class III PI3K results in weakened autophagy. Rapamycin potentiates sevoflurane-induced autophagy and 3-MA inhibits autophagy induced by sevoflurane. Hence, sevoflurane may initiate autophagy through inhibiting mTOR or activating the Class III PI3K pathway. The relationship of function between apoptosis and autophagy is complicated. Through their shared regulation by similar molecular regulators, they can suppress or act synergistically each other for example the Bcl-2 proteins family (Nassif et al., 2014). Interestingly, we found that the levels of Bax protein and TUNEL-positive cells number significantly increased while the levels of Bcl-2 significantly decreased after exposure to 3.4% sevoflurane for 4 h x 3d in rat hippocampus. This suggests that this dosage of sevoflurane enhances the development of neuronal apoptosis and at the same time promotes neuronal autophagy. To be noted is that autophagy can, inturn, suppress the excessive development of apoptosis. The relation between sevoflurane-induced autophagy and apoptosis is worth further investigation.