HDAC3 of dorsal hippocampus induces postoperative cognitive dysfunction in aged mice

Yang, Li; Hao, Jing‐Ru; Gao, Yin; Yang, Xiu Hong; Shen, Xiaoran; Wang, Hu-Yi; Sun, Nan; Gao, Can

doi:10.1016/j.bbr.2022.114002

Cited by 12 publications

(16 citation statements)

References 62 publications

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“…Anesthesia and surgery are performed simultaneously in clinical scenario. The current literature supports the perspective that the duration and depth of anesthesia, but not volatile anesthetics, are risk factors for POCD. , Growing evidence from rodent models has revealed that surgery is a more prominent contributor to neuroinflammation and cognitive impairments compared to inhalational anesthetics. , Laparotomy but not isoflurane exposure alone impaired memory performance . According to the overwhelming majority of POCD studies, , the isoflurane exposure alone group was not designed in this study.…”

Section: Discussionmentioning

confidence: 53%

“…23,24 Growing evidence from rodent models has revealed that surgery is a more prominent contributor to neuroinflammation and cognitive impairments compared to inhalational anesthetics. 25,26 Laparotomy but not isoflurane exposure alone impaired memory performance. 26 According to the overwhelming majority of POCD studies, 27,28 the isoflurane exposure alone group was not designed in this study.…”

Section: ■ Discussionmentioning

confidence: 97%

“…25,26 Laparotomy but not isoflurane exposure alone impaired memory performance. 26 According to the overwhelming majority of POCD studies, 27,28 the isoflurane exposure alone group was not designed in this study.…”

Section: ■ Discussionmentioning

confidence: 97%

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Inhibition of PINK1-Mediated Mitophagy Contributes to Postoperative Cognitive Dysfunction through Activation of Caspase-3/GSDME-Dependent Pyroptosis

Wang

Zhao

Gao

et al. 2023

ACS Chem. Neurosci.

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PTEN-induced kinase 1 (PINK1)-mediated mitophagy and caspase-1/gasdermin D canonical pyroptosis pathways have been implicated in the pathogenesis of postoperative cognitive dysfunction (POCD). However, gasdermin E (GSDME), another recently identified executioner of pyroptosis that can be specifically cleaved by caspase-3, is highly expressed in the brain and neurons. This study aimed to ascertain whether PINK1-dependent mitophagy governs postoperative cognitive capacity through caspase-3/GSDME. Twelve month old male Sprague-Dawley rats underwent exploratory laparotomy under isoflurane anesthesia. Lipopolysaccharide (LPS)-primed SH-SY5Y cells were used to mimic postsurgical neuroinflammation. For the interventional study, rats were administered with adeno-associated virus serotype 9 (AAV9)-mediated silencing of Pink1 and/or caspase-3 inhibitor Ac-DEVD-CHO (Ac-DC). SH-SY5Y cells were treated with siPINK1 and/or Ac-DC. Cognitive performance was assessed using the Morris water maze test. The mitophagy-and pyroptosis-related parameters were determined in the hippocampus and SH-SY5Y cells. Anesthesia/surgery and LPS caused defective PINK1-mediated mitophagy and activation of caspase-3/GSDME-dependent pyroptosis. AAV-9 mediated Pink1 overexpression mitigated cognitive impairment and caspase-3/ GSDME-dependent pyroptosis. Conversely, inhibition of PINK1 aggravates POCD and overactivates neuronal pyroptosis. These abnormalities were rescued by Ac-DC treatment. Collectively, PINK1-mediated mitophagy regulates anesthesia and surgery-induced cognitive impairment by negatively affecting the caspase-3/GSDME pyroptosis pathway, which provides a promising therapeutic target for POCD.

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Section: Discussionmentioning

confidence: 53%

Section: ■ Discussionmentioning

confidence: 97%

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Inhibition of PINK1-Mediated Mitophagy Contributes to Postoperative Cognitive Dysfunction through Activation of Caspase-3/GSDME-Dependent Pyroptosis

Wang

Zhao

Gao

et al. 2023

ACS Chem. Neurosci.

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“…Therefore, regardless of age, human patients with pathophysiological conditions involving dysregulated stress response systems, inflammation, and neurodegenerative changes may be at increased risk of developing PND after undergoing surgery under GA, or after exposure to GAs alone. Emerging data from laboratory and clinical studies suggest that epigenetic mechanisms may play a crucial role in anesthesia, surgery-induced stress and inflammatory responses, and neurocognitive abnormalities that constitute PND [ 268 , 269 ].…”

Section: Pathogenesis Of Pndmentioning

confidence: 99%

“…In contrast to DNA methylation, which reduces gene transcription, histone acetylation promotes gene transcription by relaxing the charged attraction between histones and DNA, thereby permitting access of transcription factors or RNA polymerase to DNA [ 318 , 319 , 320 ]. A number of studies reported that the dysregulation of hippocampal histone acetylation might contribute to surgery-induced cognitive impairments, whereas restoration of histone acetylation by HDAC inhibitors or environmental enrichment may exert neuroprotective effects [ 268 , 321 , 322 , 323 ]. For example, Jia and colleagues found that an exploratory laparotomy in 16-, but not in 3-month-old, mice impaired hippocampus-dependent long-term memory.…”

Section: Pathogenesis Of Pndmentioning

confidence: 99%

Intergenerational Perioperative Neurocognitive Disorder

Morey

Seubert

et al. 2023

Biology

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Accelerated neurocognitive decline after general anesthesia/surgery, also known as perioperative neurocognitive disorder (PND), is a widely recognized public health problem that may affect millions of patients each year. Advanced age, with its increasing prevalence of heightened stress, inflammation, and neurodegenerative alterations, is a consistent contributing factor to the development of PND. Although a strong homeostatic reserve in young adults makes them more resilient to PND, animal data suggest that young adults with pathophysiological conditions characterized by excessive stress and inflammation may be vulnerable to PND, and this altered phenotype may be passed to future offspring (intergenerational PND). The purpose of this narrative review of data in the literature and the authors’ own experimental findings in rodents is to draw attention to the possibility of intergenerational PND, a new phenomenon which, if confirmed in humans, may unravel a big new population that may be affected by parental PND. In particular, we discuss the roles of stress, inflammation, and epigenetic alterations in the development of PND. We also discuss experimental findings that demonstrate the effects of surgery, traumatic brain injury, and the general anesthetic sevoflurane that interact to induce persistent dysregulation of the stress response system, inflammation markers, and behavior in young adult male rats and in their future offspring who have neither trauma nor anesthetic exposure (i.e., an animal model of intergenerational PND).

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Depletion of PIEZO1 expression is accompanied by upregulating p53 signaling in mice with perioperative neurocognitive disorder

Bai,

Huang,

Long

et al. 2023

Funct Integr Genomics

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As the common complications observed in surgical elder patients, perioperative neurocognitive disorders (PND) cause a series of serious perioperative health problems. However, there are no effective treatments, and the exact mechanisms are still largely unknown. In this study, transcriptome sequencing was performed to investigate the differentially expressed genes (DEGs)in the hippocampus of C57BL/6J aged mice with or without PND. Compared with the Mock group, the expression of 352, 395, and 772 genes changed signi cantly in the PND group at day 1, 7, and 21 after surgery, respectively. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) showed that DEGs were mainly associated with p53 signaling. Moreover, GSEA revealed that potentially p53-related DEGs such as leucine-rich repeat serine/threonineprotein kinase 1 (LRRK1), monooxygenase DBH-like 1 (MOXD1), and piezo type mechanosensitive ion channel component 1 (PIEZO1). Furthermore, we con rmed the decreased interaction of PIEZO1 with p53 in PND, and upregulation of PIEZO1 resulted in a decrease in p53 protein levels through increased ubiquitination of p53. In conclusion, this study contributes to the knowledge of global changes in gene expression and mechanisms during PND.

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HDAC3 of dorsal hippocampus induces postoperative cognitive dysfunction in aged mice

Cited by 12 publications

References 62 publications

Inhibition of PINK1-Mediated Mitophagy Contributes to Postoperative Cognitive Dysfunction through Activation of Caspase-3/GSDME-Dependent Pyroptosis

Inhibition of PINK1-Mediated Mitophagy Contributes to Postoperative Cognitive Dysfunction through Activation of Caspase-3/GSDME-Dependent Pyroptosis

Intergenerational Perioperative Neurocognitive Disorder

Depletion of PIEZO1 expression is accompanied by upregulating p53 signaling in mice with perioperative neurocognitive disorder

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