MANF Alleviates Sevoflurane-Induced Cognitive Impairment in Neonatal Mice by Modulating Microglial Activation and Polarization

Gao, Jie; Zhang, Huiping; Zhou, Leiying; Liu, Jiaqi; Zhuo, Enba; Shen, Yujun; Liu, Xuesheng; Shen, Qiying

doi:10.1007/s12035-023-03792-z

Cited by 1 publication

(1 citation statement)

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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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