Sevoflurane exposure causes neuronal apoptosis and cognitive dysfunction by inducing ER stress via activation of the inositol 1, 4, 5-trisphosphate receptor

Zhang, Qi; Li, Yanan; Yin, Chunyue; Zhou, Qi; Guo, Junfei; Zhao, Juan; Xian, Xiaohui; Hou, Zhiyong; Wang, Qiujun

doi:10.3389/fnagi.2022.990679

Cited by 8 publications

(4 citation statements)

References 40 publications

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“…It is more likely that SYR prevents further degeneration and supports the survival of existing neurons, rather than promoting the regeneration of new cells after neuronal loss. This is corroborated by the study, which found that sevoflurane exposure causes neuronal apoptosis and cognitive dysfunction by inducing endoplasmic reticulum (ER) stress via IP3R activation in aged rats and isolated hippocampal neurons ( 16 ). The ability of SYR to modulate these pathways and prevent neuronal apoptosis underscores its potential as a neuroprotective agent against sevoflurane-induced neurotoxicity ( 17 ).…”

Section: Discussionsupporting

confidence: 55%

Syringaresinol attenuates Tau phosphorylation and ameliorates cognitive dysfunction induced by sevoflurane in aged rats

Zheng,

Teng,

Liu

et al. 2024

Journal of Neuropathology &Amp; Experimental Neurology

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Cognitive dysfunction following anesthesia with agents such as sevoflurane is a significant clinical problem, particularly in elderly patients. This study aimed to explore the protective effects of the phytochemical syringaresinol (SYR) against sevoflurane-induced cognitive deficits in aged Sprague-Dawley rats and to determine the underlying mechanisms involved. We assessed the impact of SYR on sevoflurane-induced cognitive impairment, glial activation, and neuronal apoptosis through behavioral tests (Morris water maze), immunofluorescence, Western blotting for key proteins involved in apoptosis and inflammation, and enzyme-linked immunosorbent assays for interleukin-1β, tumor necrosis factor-α, and interleukin-6. SYR treatment mitigated sevoflurane-induced cognitive decline, reduced microglial and astrocyte activation (decreased Iba-1 and GFAP expression), and countered neuronal apoptosis (reduced Bax, cleaved-caspase3, and cleaved-PARP expression). SYR also enhanced Sirtuin-1 (SIRT1) expression and reduced p-Tau phosphorylation; these effects were reversed by the SIRT1 inhibitor EX527. SYR exerts neuroprotective effects on sevoflurane-induced cognitive dysfunction by modulating glial activity, apoptotic signaling, and Tau phosphorylation through the SIRT1 pathway. These findings could inform clinical strategies to safeguard cognitive function in patients undergoing anesthesia.

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Section: Discussionsupporting

confidence: 55%

Syringaresinol attenuates Tau phosphorylation and ameliorates cognitive dysfunction induced by sevoflurane in aged rats

Zheng,

Teng,

Liu

et al. 2024

Journal of Neuropathology &Amp; Experimental Neurology

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“…Accumulating evidence revealed that sevo urane exposure may induce persistent cognitive de cits in neonatal brains of various animals, which correlated with death of hippocampal neurons caused by a variety of pathological processes including neuroin ammation and neuronal apoptosis (Gao et al 2023;Xu et al 2023a;Zhang et al 2022b;Zhou et al 2023b). Present study showed that spatial memory de cits following repeated sevo urane exposure were linked to hippocampal neuronal death triggered by iron-mediated lipid peroxidation in neonatal mice (Wu et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Sevoflurane exposure triggers ferroptosis of neuronal cells initiated by the activation of ATM/p53 in the neonatal brain via JNK/p38 MAPK-mediated oxidative DNA damage

Gu,

Pan,

Wang

et al. 2024

Preprint

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The safety of volatile anesthetic exposure in an early life has attracted widespread concern on its potential developmental neurotoxicity. Neuronal death has been regarded as the pivotal pathological factor related to neurotoxic effect caused by volatile anesthetic sevoflurane in the neonatal brain, but the detailed mechanism remains controversial. Ferroptosis is a novel type of regulated cell death driven by excess lipid peroxidation secondary to intracellular iron overload, and implicated in the pathogenesis progression of various neurological disorders. Acting as a death messenger, p53 is mainly activated by ATM during DNA damage, and functions to mediate diverse types of cell death including apoptosis, autophagy and ferroptosis. JNK/p38 MAPK have been proposed important stress-responsive pathways to exacerbate intracellular ROS production, linking DNA damage to many pathological conditions such as neurodegeneration and ischemic injury. Here, we focused on the role of activated ATM/p53-mediated ferroptosis in neuronal death caused by sevoflurane in neonatal brain and elucidated its underlying mechanisms. Our present study demonstrated that sevoflurane exposure-triggered neuronal death was correlated with intracellular iron overload and lipid peroxidation in vitro and in vivo, which was in accordance with the typical features of ferroptosis. Furthermore, we found that neuronal death caused by sevoflurane was associated with ATM/p53 activation in response to DNA damage. Suppressing ATM/p53 pathway counteracted iron-dependent lipid peroxidation, which inhibited neonatal neuronal ferroptosis triggered by sevoflurane. Additionally, sevoflurane exposure resulted in JNK/p38 MAPK activation, followed by intracellular ROS accumulation, leading to DNA damage. Mechanistically, ATM/p53 contributed to neonatal neuronal ferroptosis caused by sevoflurane via two pathways, one is to increase intracellular ferrous iron through upregulating TFR and downregulating FPN, the other is to promote lipid peroxidation via activating NOX4, ALOX12 and ALOX15 and suppressing SLC7A11. Collectively, these findings demonstrated that sevoflurane exposure induced ferroptosis of neuronal cells in the neonatal brain, which was triggered by the ATM/p53 activation via JNK/p38 MAPK-mediated ROS accumulation and resultant DNA damage.

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“… 9 10 The changes in the cytosol calcium level will induce a signal transmission in excitable and nonexcitable cells; thus promoting the excitatory pathway. 8 The inhibitory activity will stay dominant throughout anesthesia; thus, the excitatory manifestation will not be seen. However, after the anesthesia agent exposure is ceased, the stimulation of the gamma amino butyric acid receptors will decrease, meanwhile a high cytosol level of calcium is sustained, causing an increase in the excitatory pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Exposure to sevoflurane is an external factor that induces the activation inositol 1,4,5-triphosphate (InsP3) receptors that stimulates the release of calcium from the calcium-sensitive storage of the endoplasmic reticulum (ER). 8 An excess amount of intracellular calcium is thought to trigger a hyperexcitability state in neurons, as it does in the cardiac muscle, resulting in emergence delirium.…”

Section: Introductionmentioning

confidence: 99%

Possible role of high calcium concentrations in rat neocortical neurons in inducing hyper excitatory behavior during emergence from sevoflurane: a proposed pathophysiology

Ramlan,

Madjid,

Hanindito

et al. 2023

Medical Gas Research

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Sevoflurane has been shown to increase the incidence of emergence delirium in children; however, the mechanism remains unclear. Sevoflurane increases cytoplasmic calcium concentration which in turn may play a role in emergence delirium. This study aimed to investigate the level of intracellular calcium in rats experiencing hyperexcitatory behavior after exposure to sevoflurane, as well as the role of magnesium in preventing this phenomenon. After ethical approval, 2-5-week-old Sprague-Dawley rats (n = 34) were insufflated with sevoflurane in a modified anesthesia chamber. One group received magnesium sulphate intraperitoneally. After termination of sevoflurane exposure, the occurrence of hyperexcitation was observed. Brain tissue samples from the rats were studied for intracellular calcium levels under a two-channel laser scanning confocal microscope and were quantitatively calculated using ratiometric calculation. The presence of inflammation or oxidative stress reaction was assessed using nuclear factor κB and malondialdehyde. The incidence of hyperexcitatory behavior post sevoflurane exposure was 9 in 16 rats in the observation group and none in the magnesium group. Tests for inflammation and oxidative stress were within normal limits in both groups. The rats showing hyperexcitation had a higher level of cytosol calcium concentration compared to the other groups. To conclude, the calcium concentration of neocortical neurons in Sprague-Dawley rats with hyperexcitatory behavior is increased after exposure to sevoflurane. Administration of magnesium sulphate can prevent the occurrence of hyperexcitation in experimental animals.

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Sevoflurane exposure causes neuronal apoptosis and cognitive dysfunction by inducing ER stress via activation of the inositol 1, 4, 5-trisphosphate receptor

Cited by 8 publications

References 40 publications

Syringaresinol attenuates Tau phosphorylation and ameliorates cognitive dysfunction induced by sevoflurane in aged rats

Syringaresinol attenuates Tau phosphorylation and ameliorates cognitive dysfunction induced by sevoflurane in aged rats

Sevoflurane exposure triggers ferroptosis of neuronal cells initiated by the activation of ATM/p53 in the neonatal brain via JNK/p38 MAPK-mediated oxidative DNA damage

Possible role of high calcium concentrations in rat neocortical neurons in inducing hyper excitatory behavior during emergence from sevoflurane: a proposed pathophysiology

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