Cdh1-Mediated Metabolic Switch from Pentose Phosphate Pathway to Glycolysis Contributes to Sevoflurane-Induced Neuronal Apoptosis in Developing Brain

Abstract

Cdh1 is a regulatory subunit of the anaphase promoting complex/cyclosome (APC/C), known to be involved in regulating neuronal survival. The role of Cdh1 in volatile anesthetics-induced neuronal apoptosis in the developing brain is unknown. In this study, we used postnatal day 7 (P7) and day 21 (P21) mice exposed to 2.3% sevoflurane for 6 h to investigate at which age and duration of exposure sevoflurane affects the expression of Cdh1 and glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and that of the pentose phosphate pathway (PPP) enzyme, glucose-6-phosphate dehydrogenase (G6PD). Furthermore, we tested whether the cyclin-dependent kinases (cdks) inhibitor roscovatine could counteract the effects caused by exposure to sevoflurane. Finally, we applied the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO), G6PD inhibitor dehydroepiandrosterone (DHEA), and exogenous reduced glutathione to examine the contribution of the glycolysis pathway and PPP to sevoflurane-induced neuroapoptosis. We found that prolonged sevoflurane anesthesia significantly reduces the Cdh1 level in P7 mice compared to in the P21 ones; moreover, the decrease in Cdh1 level results in a switch in glucose metabolism from the PPP to neuronal glycolysis. This leads to an imbalance between reactive oxygen species production and reduced glutathione level in the developing brain, which is more susceptible to oxidative stress. As a result, sevoflurane induces neuroapoptosis through Cdh1-mediated glucose metabolism reprogramming. Our study demonstrates a critical role of Cdh1 in sevoflurane-induced neuroapoptosis by shifting PPP to the glycolytic pathway in the developing brain. These findings suggest that Cdh1 may be a novel target for preventing volatile anesthetics-induced neurotoxicity and memory impairment.

Sevoflurane Exposure Induces Neuronal Cell Parthanatos Initiated by DNA Damage in the Developing Brain via an Increase of Intracellular Reactive Oxygen Species

“…Compared to the adult brain, the neonatal brain has a high level of mitochondrial respiration for oxygen consumption and low concentrations of antioxidants, which makes it particularly sensitive to the devastating consequences of oxidative stress (Bhat et al, 2015;Wu et al, 2019). Accumulating evidence has suggested that oxidative stress may contribute to sevofluraneinduced neurotoxicity in the developing brain (Yonamine et al, 2013;Liu et al, 2019). In a neonatal rat model, sevoflurane exposure could induce intracellular ROS production through associating with mitochondrial dysfunction and activation of NADPH oxidase, which results in widespread neurodegeneration and long-term behavioral impairment (Yonamine et al, 2013;Sun et al, 2016).…”

The Redox Role of G6PD in Cell Growth, Cell Death, and Cancer

“…G6PD inhibition induces in vitro and in vivo chemotherapeutic cytotoxicity in AML cells, demonstrating that high mTORC1 expression may be a target for G6PD inhibition. Unlike in cancer cell studies, the metabolic switch is also important in neuronal development [244]. Cdh1 is involved in regulating neuronal survival, especially in volatile anesthetic-induced neuronal apoptosis.…”

Metabolic Drivers of Invasion in Glioblastoma

“…In addition to their influence via integrins, several metabolites and metabolic pathways have direct effects on tumor cell adhesion properties. Upregulation of glycolysis and the PPP have both been associated with the functional activity of the adhesion proteins E-cadherin and P- cadherin ( Liu et al, 2019 ; Sousa et al, 2019 ). Furthermore, increased levels of the metabolite Acetyl-coA directly promote cell-ECM adhesion by donating the necessary acetyl group for lysine acetylation in cross-linking ( Lee et al, 2018 ).…”