Cyclophilin D Contributes to Anesthesia Neurotoxicity in the Developing Brain

Zhang, Yiying; Lü, Ping; Liang, Feng; Liufu, Ning; Dong, Yuanlin; Zheng, Jialin; Xie, Zhongcong

doi:10.3389/fcell.2019.00396

Cited by 17 publications

(28 citation statements)

References 44 publications

(61 reference statements)

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“…Multiple lines of evidence support the importance of hippocampal mitochondrial homeostasis in the development of dNCR after anesthesia and surgery, although the precise mechanisms merit additional exploration [ 5 , 8 ]. We reasoned that mitochondria might play a key role in preventing cognitive impairment after anesthesia and surgery.…”

Section: Resultsmentioning

confidence: 99%

“…To support normal cerebral function, the brain has a high energy demand in the form of ATP, which is supplied by mitochondria. There is significant evidence supporting the concept that maintaining mitochondrial homeostasis in neuronal cells is essential for the prevention and treatment of dNCR [ 5 , 7 , 40 ]. The objective of our current study was to identify the specific role of mitochondrial α -syn accumulation on neurotoxicity and cognition in aged mice following sevoflurane anesthesia plus surgery and also in cultured neurons exposed to LPS ( Figure 9 ).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

Yuan

et al. 2021

Oxidative Medicine and Cellular Longevity

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Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha-synuclein (α-syn; encoded by the gene, SNCA) has recently been shown to play an important role in hippocampus-dependent working memory. Aggregated forms of α-syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α-syn improved both mitochondrial function and mitochondria-dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α-syn (including total α-syn, phosphorylated-Ser129-α-syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna. Clenbuterol significantly attenuated surgery-induced progressive accumulation of various toxic α-syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α-syn accumulation and increased mitochondria-mediated apoptosis in vitro using nerve growth factor-differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α-syn inhibition, we used a lentiviral Snca-shRNA (Lv-shSnca) to knockdown Snca. Of note, Lv-shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α-syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α-syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α-syn for dNCR.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

Yuan

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…And the others believe the increased Ca 2+ is from the membrane Ca 2+ channel, since nimodipine can block the increase of Ca 2+ and the dysfunction of mitochondria [ 33 ]. The increase of intracellular calcium flux and ROS level could stimulate the opening of mPTP, decrease MMP, and suppress ATP synthesis, subsequently leading to neuroapoptosis by the mitochondrial pathway [ 33 , 44 ].…”

Section: Apoptosis In Neural Cells By Sevoflurane Through Mitochonmentioning

confidence: 99%

[Retracted] Involvement of Mitochondrial Dynamics and Mitophagy in Sevoflurane‐Induced Cell Toxicity

Guo

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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General anesthesia is a powerful and indispensable tool to ensure the accomplishment of surgical procedures or clinical examinations. Sevoflurane as an inhalational anesthetic without unpleasant odor is commonly used in clinical practice, especially for pediatric surgery. However, the toxicity caused by sevoflurane has gained growing attention. Mitochondria play a key role in maintaining cellular metabolism and survival. To maintain the stability of mitochondrial homeostasis, they are constantly going through fusion and fission. Also, damaged mitochondria need to be degraded by autophagy, termed as mitophagy. Accumulating evidence proves that sevoflurane exposure in young age could lead to cell toxicity by triggering the mitochondrial pathway of apoptosis, inducing the abnormalities of mitochondrial dynamics and mitophagy. In the present review, we focus on the current understanding of mitochondrial apoptosis, dynamics and mitophagy in cell function, the implications for cell toxicity in response to sevoflurane, and their underlying potential mechanisms.

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“…4.1% sevoflurane was commonly used in NSCs to explore the neurotoxicity of SEV in vitro in previous studies [35,38]. There are other studies [39,40] using 3% SEV in vivo and 4.1% SEV in vitro to investigate the mechanism of SEV. The results showed that during mid-trimester, multiple exposures to sevoflurane can cause premature differentiation of NSCs in developing brains of offspring.…”

Section: Discussionmentioning

confidence: 99%

Maternal sevoflurane exposure affects differentiation of hippocampal neural stem cells by regulating miR-410-3p and ATN1

Zhang

et al. 2020

Stem Cell Res Ther

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Background Currently, numerous animal studies have shown that exposure to commonly used general anesthetics during pregnancy may cause neurocognitive impairment in the offspring. Reportedly, exposure to sevoflurane during mid-trimester of pregnancy can inhibit proliferation of neural stem cells (NSCs) and lead to early apoptosis. Whether exposure to sevoflurane during pregnancy affects the differentiation of NSCs remains unclear. Methods In the present study, pregnant rats were exposed to 3% sevoflurane once for 2 h on gestational day 14 (G14) or 3 times for 2 h on G13, G14, and G15. Next, the differentiation of NSCs was measured using neuron marker β-tubulin III and astrocyte marker glial fibrillary acidic protein (GFAP) in fetal brain tissues 24 h and 72 h after anesthesia and in hippocampus on postnatal day 28. Primary cultured rat NSCs were exposed to 4.1% sevoflurane to explore the mechanism. Results The results showed that during mid-trimester, multiple exposures to sevoflurane can cause premature differentiation of NSCs in developing brains of offspring and lead to long-term neuron reduction and astrocyte proliferation in hippocampus. The data from the present study indicated that repeated exposure to sevoflurane downregulated atrophin-1 (ATN1) expression and caused early differentiation of NSCs. Overexpression of ATN1 via lentivirus transfection attenuated the influence of sevoflurane. Using dual luciferase assay, ATN1 was found to be a target gene of microRNA-410-3p (miR-410-3p). MiR-410-3p suppression via lentivirus transfection recovered the ATN1 expression and differentiation of NSCs. Conclusions The results from the present study demonstrated that repeated exposure to sevoflurane leads to early differentiation of NSCs and long-term effects via the miR-410-3p/ATN1 pathway.

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Cyclophilin D Contributes to Anesthesia Neurotoxicity in the Developing Brain

Cited by 17 publications

References 44 publications

Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

[Retracted] Involvement of Mitochondrial Dynamics and Mitophagy in Sevoflurane‐Induced Cell Toxicity

Maternal sevoflurane exposure affects differentiation of hippocampal neural stem cells by regulating miR-410-3p and ATN1

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