Inhibiting NLRP3 inflammasome with MCC950 ameliorates perioperative neurocognitive disorders, suppressing neuroinflammation in the hippocampus in aged mice

Fu, Qun; Li, Jing; Qiu, Lili; Ruan, Jiaping; Mao, Min; Li, Shu-Ming; Mao, Qinghong

doi:10.1016/j.intimp.2020.106317

Cited by 42 publications

(28 citation statements)

References 55 publications

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“…Assembly of the NLRP3 inflammasome triggers cleavage of caspase-1 and induces maturation of the proinflammatory cytokines IL-1β and IL-18, and subsequent cleavage of GSDMD and pyroptotic cell death (Man et al, 2017 ; Shi et al, 2017 ; Voet et al, 2019 ). Our results showed that surgery-induced upregulation of NLRP3 and cleaved caspase-1, and secretion of IL-1β and IL-18, in the hippocampus in aged mice, in agreement with the results of previous studies (Peng et al, 2019 ; Fu et al, 2020 ). Furthermore, surgery-induced upregulation of the GSDMD N domain, the key biomarker of pyroptosis, and the surgery group exhibited more ruptured and TUNEL-positive neurons, a morphological characteristic of pyroptosis.…”

Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

“…The NLRP3 inflammasome is the best-characterized member of the NLRP family, which consists of the NLRP3 protein, apoptosis-associated speck-like proteins, and precursor caspase-1 (Pro-caspase-1). The NLRP3 inflammasome has major roles in PND through triggering the release of IL-1β and IL-18 via active caspase-1 (Fan et al, 2018 ; Fu et al, 2020 ). To investigate whether protecting mitochondria with elamipretide might inhibit surgery-induced activation of the NLRP3 inflammasome-caspase-1 pathway, we measured the protein levels of NLRP3, pro-caspase-1, and cleaved caspase-1, and the number of caspase-1 positive cells in the hippocampal CA1 area.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown that cognitive deficits induced by surgery in aged mice can be observed on postoperative day 7 (Fu et al, 2020;Qiu et al, 2020). We used open field tests to FIGURE 2 | Effects of elamipretide on the canonical nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1 pathway in the hippocampus in aged mice after surgery.…”

Section: Elamipretide Attenuates Surgery-induced Cognitive Deficits Imentioning

confidence: 99%

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Elamipretide Attenuates Pyroptosis and Perioperative Neurocognitive Disorders in Aged Mice

Zuo

Yin

Cheng

et al. 2020

Front. Cell. Neurosci.

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Pyroptosis is a recently characterized inflammatory form of programmed cell death that is thought to be involved in the pathogenesis of perioperative neurocognitive disorders (PND). Elamipretide (SS-31), a mitochondrial-targeted peptide with multiple pharmacological properties, including anti-inflammatory activity, has been demonstrated to protect against many neurological diseases. However, the effect of elamipretide on pyroptosis in PND has not been studied. We established an animal model of PND by performing an exploratory laparotomy on mice under isoflurane anesthesia and examined the effects of elamipretide on cognitive function, synaptic integrity, neuroinflammation, mitochondrial function, and signaling controlling pyroptosis. Our results showed that anesthesia and surgery caused mitochondrial dysfunction and abnormal morphology, activation of canonical nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1 dependent pyroptosis, and downregulation of synaptic integrity-related proteins in the hippocampus in aged mice, thus leading to learning and memory deficits in behavioral tests. Remarkably, treatment with the mitochondrial-targeted peptide elamipretide not only had protective effects against mitochondrial dysfunction but also attenuated surgery-induced pyroptosis and cognitive deficits. Our results provide a promising strategy for the treatment of PND involving mitochondrial dysfunction and pyroptosis.

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Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Elamipretide Attenuates Surgery-induced Cognitive Deficits Imentioning

confidence: 99%

See 2 more Smart Citations

Elamipretide Attenuates Pyroptosis and Perioperative Neurocognitive Disorders in Aged Mice

Zuo

Yin

Cheng

et al. 2020

Front. Cell. Neurosci.

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“…Exploratory laparotomy under the anesthesia of iso urane is a common approach to induce PND in aged mice [32,33], which simulates clinical status closely. Therefore, this approach was chosen to establish the animal model of PND.…”

Section: Discussionmentioning

confidence: 99%

Galectin-1 ameliorates perioperative neurocognitive disorders in aged mice

Wu¹,

Song²,

Shen³

et al. 2020

Preprint

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Background The incidence of perioperative neurocognitive disorders (PND) is higher in the elderly patients undergoing surgery. Microglia activation-mediated neuroinflammation is one of the hallmarks of PND. Galectin-1 has been identified as pivotal modulator in central nervous system (CNS), while the role of galectin-1 in PND induced by microglia-mediated neuroinflammation is still undetermined. Methods An exploratory laparotomy model anesthetized with isoflurane was employed to investigate the role of galectin-1 on PND in aged mice. Open field test and Morris water maze were used to test the cognitive function 3 or 7 days after surgery. Immunofluorescence staining was employed to detect the activation of microglia and neuronal integrity in the hippocampus of aged mice. Enzyme-linked immunosorbent assay (ELISA), reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to elucidate the underlying mechanisms. Results Pretreatment with galectin-1 attenuated the cognitive dysfunction induced by surgery in aged mice and inhibited microglial activity. Moreover, galectin-1 decreased the expression level of inflammatory proteins (interleukin-1β, interleukin-6 and tumor necrosis factor-α), and disrupted neuronal integrity in hippocampus. Galectin-1 inhibited the inflammation of BV2 microglial cells induced by lipopolysaccharide via decreasing the translocation of c-Jun and NF-κB p65, while this kind of inhibition was rescued when overexpressing IRAK1. Conclusions Our findings provide evidence that galectin-1 may inhibit IRAK1 expression, thus suppressing inflammatory response, inhibiting neuroinflammation, and improving ensuing cognitive dysfunction. Collectively, these findings unveil that galectin-1 may elicit protective effect on surgery-induced neuroinflammation and neurocognitive disorders.

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Leveraging the ATP‐P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications

Yin

Wei

Caseley

et al. 2023

Medicinal Research Reviews

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The P2X7 receptor is an exceptional member of the P2X purinergic receptor family, with its activation requiring high concentrations of extracellular adenosine 5ʹ‐triphosphate (ATP) that are often associated with tissue damage and inflammation. In the central nervous system (CNS), it is highly expressed in glial cells, particularly in microglia. In this review, we discuss the role and mechanisms of the P2X7 receptor in mediating neuroinflammation and other pathogenic events in a variety of traumatic CNS damage conditions, which lead to loss of neurological and cognitive functions. We raise the perspective on the steady progress in developing CNS‐penetrant P2X7 receptor‐specific antagonists that leverage the ATP‐P2X7 receptor signaling axis as a potential therapeutic strategy to alleviate traumatic CNS damage and related complications.

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Inhibiting NLRP3 inflammasome with MCC950 ameliorates perioperative neurocognitive disorders, suppressing neuroinflammation in the hippocampus in aged mice

Cited by 42 publications

References 55 publications

Elamipretide Attenuates Pyroptosis and Perioperative Neurocognitive Disorders in Aged Mice

Elamipretide Attenuates Pyroptosis and Perioperative Neurocognitive Disorders in Aged Mice

Galectin-1 ameliorates perioperative neurocognitive disorders in aged mice

Leveraging the ATP‐P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications

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