The Effects of Anesthesia on Autophagic Degradation

Autophagy is a critical cellular process that allows organisms to maintain homeostasis by recycling and degrading proteins that are no longer functional or needed¹. Autophagosomes, which are double membrane vesicles, surround and deliver nonfunctional proteins to either lysosomes in animals or vacuoles in plants and yeasts². Recent studies have shown that anesthetic drugs can modulate autophagic degradation by affecting intracellular Ca2+ levels via InsP3R receptors on the endoplasmic reticulum³. Modulated autophagy by anesthetic agents can increase cell survival and protection.

Ischemia during cardiac surgery occurs when insufficient oxygen travels to the heart and can be lethal. Volatile anesthetics trigger cardiac preconditioning and protect from ischemic-reperfusion injury⁴. Anesthetic preconditioning of the myocardium has also been linked to autophagy. For example, a study showed that sevoflurane preconditioning led to formation of autophagosomes in rat myocardium, successfully protecting against ischemia⁵. In another study, ischemia-reperfusion injury was induced in the rat myocardium, then the tissue was treated with either saline, propofol, or intralipid. When treated with propofol, an intravenous agent commonly utilized in general anesthesia, autophagic degradation was inhibited and myocardial infarction size decreased due to reduced autophagic cell death⁶ The two different examples demonstrate that cardiac autophagy can either be upregulated or downregulated by anesthetic agents for defense against ischemia.

Similarly, cerebral ischemia-reperfusion injury is the result of insufficient oxygen supply to the brain and can lead to severe functional impairment⁷. Propofol is widely known as a neuroprotective agent due to its ability to prevent autophagic cell death during ischemia-reperfusion injury in the hippocampus. Cui et al. showed that propofol inhibits the p53 pathway, which subsequently inhibits autophagosome production. Since excessive autophagic degradationis harmful for neurons in the hippocampus, propofol successfully eliminates the undesirable consequences of autophagy during ischemia⁸. Furthermore, studies show that patients with depression who are treated with electroconvulsive therapy (ECT) are at risk of developing learning disabilities and memory loss. Propofol reduced the side effects of ECT, suggesting that those side effects are directly related to excessive autophagic degradation⁹

The protective ability of anesthetic drugs is evident; however, physicians must be aware that this is not always the case. Under certain conditions, the effect of anesthetic agents on autophagy may be detrimental. In one study, researchers revealed that use of 1.5% isoflurane for 4 hours on rats resulted in autophagy activation, causing apoptosis and learning impairment. They discovered high levels of beclin-1 and LC3B-II, which are markers for induced autophagy. Whenisoflurane was only administered for 1 hour, this side effect was not present¹⁰. Kashiwagi et al. made the connection between anesthetics and muscle atrophy. Prolonged use of anesthetics such as pentobarbital upregulates muscle autophagy, providing complications for high-risk patients who already suffer from myopathies and dystrophies¹¹. Anesthetics may modulate autophagy positively in many cases, but these cases serve as reminders that there are exceptions. Each case must be properly examined before anesthetics are administered.

References

1. Shiomi M, Miyamae M, Takemura G, et al. Eur J Pharmacol. 2014; 724:58-66.2.

2. Nakatogawa H. (2020). Autophagic degradation of the endoplasmic reticulum. Proceedings of the Japan Academy. Series B, Physical and biological sciences, 96(1), 1–9. https://doi.org/10.2183/pjab.96.001.

3. Ren G, Zhou Y, Liang G, et al. General Anesthetics Regulate Autophagy via Modulating the Inositol 1,4,5-Trisphosphate Receptor: Implications for Dual Effects of Cytoprotection and Cytotoxicity. Sci Rep 7, 12378 (2017). https://doi.org/10.1038/s41598-017-11607-0.

4. Lamberts RR, Onderwater G, Hamdani N, et al. Circulation. 2009; 120(11): S10-5.

5. Qiao S, Xie H, Wang C, Wu X, Liu H, Liu C. J Anesth. 2013; 27(2):251-60.

6. Noh HS, Shin IW, Ha JH, et al. Mol Cells. 2010; 30(5):455-60.

7. Sun B, Ou H, Ren F, et al. Propofol inhibited autophagy through Ca2+/CaMKKβ/AMPK/mTOR pathway in OGD/R-induced neuron injury. Mol Med 24, 58 (2018). https://doi.org/10.1186/s10020-018-0054-1.

8. Cui D, Wang L, Qi A, Zhou Q, Zhang X, Jiang W. PLoS One. 2012; 7(4):e35324.

9. Li P, Hao XC, Luo J, Lv F, Wei K, Min S. Propofol mitigates learning and memory impairment after electroconvulsive shock in depressed rats by inhibiting autophagy in the hippocampus. Med Sci Monit. 2016; 22:1702–1708.

10. Li ZQ, Li LX, Mo N, et al. Duration-dependent regulation of autophagy by isoflurane exposure in aged rats. Neurosci Bull. 2015; 31:505–513

11. Kashiwagi A, Hosokawa S, Maeyama Y, et al. Anesthesia with Disuse Leads to Autophagy Up-regulation in the Skeletal Muscle. Anesthesiology. 2015; 122(5):1075-1083. https://doi.org/10.1097/ALN.0000000000000561.

Autophagy is essential for cell survival through the removal of nonfunctional proteins. Anesthetic drugs can induce or inhibit this process, but must be closely monitored, as too much or too little autophagy could lead to deleterious effects. Depending on the conditions, either upregulation or inhibition of autophagy can be beneficial. Most studies present the positive effects of anesthetics on autophagy, but there are also cases in which the opposite is true. More research should be done to determine the mechanism of action and long-term effects of anesthetics on autophagy to ensure safe administration to patients.References1.Shiomi M, Miyamae M, Takemura G, Kaneda K, Inamura Y, Onishi A, Koshinuma S, Momota Y, Minami T, Figueredo VM. Eur J Pharmacol. 2014 Feb 5; 724():58-66.2.Nakatogawa H. (2020). Autophagic degradation of the endoplasmic reticulum. Proceedings ofthe Japan Academy. Series B, Physical and biological sciences, 96(1), 1–9.https://doi.org/10.2183/pjab.96.0013.Ren, G., Zhou, Y., Liang, G. et al. General Anesthetics Regulate Autophagy via Modulating theInositol 1,4,5-Trisphosphate Receptor: Implications for Dual Effects of Cytoprotection andCytotoxicity. Sci Rep7, 12378 (2017). https://doi.org/10.1038/s41598-017-11607-04.Lamberts RR, Onderwater G, Hamdani N, Vreden MJ, Steenhuisen J, Eringa EC, Loer SA,Stienen GJ, Bouwman. RA Circulation. 2009 Sep 15; 120(11 Suppl):S10-5.5.Qiao S, Xie H, Wang C, Wu X, Liu H, Liu C. J Anesth. 2013 Apr; 27(2):251-60.6.Noh HS, Shin IW, Ha JH, Hah YS, Baek SM, Kim DR. Mol Cells. 2010 Nov; 30(5):455-60.7.Sun, B., Ou, H., Ren, F. et al. Propofol inhibited autophagy through Ca2+/CaMKKβ/AMPK/mTOR pathway in OGD/R-induced neuron injury. Mol Med24, 58(2018). https://doi.org/10.1186/s10020-018-0054-18.Cui D, Wang L, Qi A, Zhou Q, Zhang X, Jiang W. PLoS One. 2012; 7(4):e35324.9.Li P, Hao XC, Luo J, Lv F, Wei K, Min S. Propofol mitigates learning and memory impairment after electroconvulsive shock in depressed rats by inhibiting autophagy in thehippocampus. Med Sci Monit. 2016;22:1702–1708.10.Li ZQ, Li LX, Mo N, et al. Duration-dependent regulation of autophagy by isofluraneexposure in aged rats. Neurosci Bull. 2015;31:505–51311.Aki Kashiwagi, Sachiko Hosokawa, Yoshihiro Maeyama, Ryusuke Ueki, Masao Kaneki, J. A. Jeevendra Martyn, Shingo Yasuhara; Anesthesia with Disuse Leads to Autophagy Up-regulation in the Skeletal Muscle. Anesthesiology 2015;122(5):1075-1083.doi: https://doi.org/10.1097/ALN.0000000000000561.