Annexin-A1 Tripeptide Attenuates Surgery-Induced Neuroinflammation and Memory Deficits Through Regulation the NLRP3 Inflammasome

Zhang, Zhiquan; Ma, Qing; Velagapudi, Ravikanth; Barclay, William E.; Rodriguiz, Ramona M.; Wetsel, William C.; Yang, Ting; Shinohara, Mari L.; Terrando, Niccolò

doi:10.3389/fimmu.2022.856254

Cited by 15 publications

(12 citation statements)

References 59 publications

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“…MM01 inhibited inflammation by preventing ASC oligomerization and pro-caspase activation in mouse peritonitis models, but its pharmacological action and safety need further confirmation ( Soriano-Teruel et al, 2021 ). U50488H is a κ-opioid receptor agonist and annexin-A1 (ANXA1) tripeptide that effectively inhibits pyroptosis and improves PNDs by targeting the NLRP3 inflammasome via an unclear mechanism ( Song et al, 2021 ; Zhang et al, 2022 ).…”

Section: Treatmentsmentioning

confidence: 99%

The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders

et al. 2023

Front. Aging Neurosci.

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Perioperative neurocognitive disorders (PNDs) are frequent complications associated with cognitive impairment during the perioperative period, including acute postoperative delirium and long-lasting postoperative cognitive dysfunction. There are some risk factors for PNDs, such as age, surgical trauma, anesthetics, and the health of the patient, but the underlying mechanism has not been fully elucidated. Pyroptosis is a form of programmed cell death that is mediated by the gasdermin protein and is involved in cognitive dysfunction disorders. The canonical pathway induced by nucleotide oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasomes contributes to PNDs, which suggests that targeting NLRP3 inflammasomes may be an effective strategy for the treatment of PNDs. Therefore, inhibiting upstream activators and blocking the assembly of the NLRP3 inflammasome may attenuate PNDs. The present review summarizes recent studies and systematically describes the pathogenesis of NLRP3 activation and regulation and potential therapeutics targeting NLRP3 inflammasomes in PNDs patients.

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Section: Treatmentsmentioning

confidence: 99%

The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders

et al. 2023

Front. Aging Neurosci.

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“…ANXA1, a member of the annexin protein superfamily that mimics the effects of glucocorticoids 14 . A number of studies have highlighted a well-established role for ANXA1 in the immune system, including regulation of microglial activation, endothelial integrity and leukocyte trafficking 15 , 16 . In transient ischemic attack, nuclear accumulation of ANXA1 in microglia was associated with microglial polarization 17 .…”

Section: Introductionmentioning

confidence: 99%

Tat-NTS peptide protects neurons against cerebral ischemia-reperfusion injury via ANXA1 SUMOylation in microglia

Zhou,

Yan,

Huang

et al. 2023

Theranostics

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Rationale: Recent studies indicate that microglial activation and the resulting inflammatory response could be potential targets of adjuvant therapy for ischemic stroke. Many studies have emphasized a well-established function of Annexin-A1 (ANXA1) in the immune system, including the regulation of microglial activation. Nevertheless, few therapeutic interventions targeting ANXA1 in microglia for ischemic stroke have been conducted. In the present study, Tat-NTS, a small peptide developed to prevent ANXA1 from entering the nucleus, was utilized. We discovered the underlying mechanism that Tat-NTS peptide targets microglial ANXA1 to protect against ischemic brain injury. Methods: Preclinical studies of ischemic stroke were performed using an oxygen-glucose deprivation and reperfusion (OGD/R) cell model in vitro and the middle cerebral artery occlusion (MCAO) animal model of ischemic stroke in vivo. Confocal imaging and 3D reconstruction analyses for detecting the protein expression and subcellular localization of microglia in vivo. Co-immunoprecipitation (Co-IP), immunoblotting, ELISA, quantitative real-time PCR (qRT-PCR), Luciferase reporter assay for determining the precise molecular mechanism. Measurement on the cytotoxicity of Tat-NTS peptide for microglia was assessed by CCK-8 and LDH assay. TUNEL staining was used to detect the microglia conditioned medium-mediated neuronal apoptosis. Adeno-associated viruses (AAVs) were injected into the cerebral cortex, striatum and hippocampal CA1 region of adult male Cx3cr1-Cre mice, to further verify the neurofunctional outcome and mechanism of Tat-NTS peptide by TTC staining, the modified Neurological Severity Score (mNSS) test, the open field test (OFT), the novel object recognition task (NORT), the Morris water maze (MWM) test, the long-term potentiation (LTP) and the Transmission electron microscopy (TEM). Results: It was observed that administration of Tat-NTS led to a shift of subcellular localization of ANXA1 in microglia from the nucleus to the cytoplasm in response to ischemic injury. Notably, this shift was accompanied by an increase in ANXA1 SUMOylation in microglia and a transformation of microglia towards an anti-inflammatory phenotype. We confirmed that Tat-NTS-induced ANXA1 SUMOylation in microglia mediated IKKα degradation via NBR1-dependent selective autophagy, then blocking the activation of the NF-κB pathway. As a result, the expression and release of the pro-inflammatory factors IL-1β and TNF-α were reduced in both in vitro and in vivo experiments. Furthermore, we found that Tat-NTS peptide's protective effect on microglia relieved ischemic neuron apoptosis. Finally, we demonstrated that Tat-NTS peptide administration, through induction of ANXA1 SUMOylation in microglia, reduced infarct volume, improved neurological function and facilitated behavioral recovery in MCAO mice. Conclusions: Our study provides evidence for a novel mechanism of Tat-NTS peptide in regu...

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“…Toll-like receptor (TLR) plays a critical role in microglial activation. The TLR4/nuclear factor kappa B (NF-κb) signaling pathway can induce the transcription activation of various inflammatory factors, ultimately leading to apoptosis of nerve cells. ,, TAK-242 inhibits lipopolysaccharide (LPS)-mediated activation of the TLR4/NF-κb pathway, which is related to protection against transient cognitive deficits in aged animals. , Early management of neuroinflammation and oxidative stress may prevent the occurrence of some neurological disorders. − With the progression of time following splenectomy, the activation of the TLR4 pathway and increases in the levels of inflammatory factors, as well as cognitive decline, are gradually reversed . However, Terrando found that the TLR4 pathway is seemingly not necessary for the occurrence of surgical trauma-induced cognitive deficits .…”

Section: Introductionmentioning

confidence: 99%

Adiponectin Attenuates Splenectomy-Induced Cognitive Deficits by Neuroinflammation and Oxidative Stress via TLR4/MyD88/NF-κb Signaling Pathway in Aged Rats

Zhang

Guo

Yang

et al. 2023

ACS Chem. Neurosci.

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Perioperative neurocognitive disorder (PND) is a common adverse event after surgical trauma in elderly patients. The pathogenesis of PND is still unclear. Adiponectin (APN) is a plasma protein secreted by adipose tissue. We have reported that a decreased APN expression is associated with PND patients. APN may be a promising therapeutic agent for PND. However, the neuroprotective mechanism of APN in PND is still unclear. In this study, 18 month old male Sprague-Dawley rats were assigned to six groups: the sham, sham + APN (intragastric (i.g.) administration of 10 μg/kg/day for 20 days before splenectomy), PND (splenectomy), PND + APN, PND + TAK-242 (intraperitoneal (i.p.) administration of 3 mg/kg TAK-242), and PND + APN + lipopolysaccharide (LPS) (i.p. administration of 2 mg/kg LPS). We first found that APN gastric infusion significantly improved learning and cognitive function in the Morris water maze (MWM) test after surgical trauma. Further experiments indicated that APN could inhibit the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κb) p65 pathway to decrease the degree of oxidative damage (malondialdehyde (MDA) and superoxide dismutase (SOD)), microgliamediated neuroinflammation (ionized calcium binding adapter molecule 1 (IBA1), caspase-1, tumor necrosis factor (TNF)-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6)), and apoptosis (p53, Bcl2, Bax, and caspase 3) in hippocampus. By using LPSspecific agonist and TAK-242-specific inhibitor, the involvement of TLR4 engagement was confirmed. APN intragastric administration exerts a neuroprotective effect against cognitive deficits induced by peripheral trauma, and the possible mechanisms include the inhibition of neuroinflammation, oxidative stress, and apoptosis, mediated by the suppression of the TLR4/MyD88/NFκb signaling pathway. We propose that oral APN may be a promising candidate for PND treatment.

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Annexin-A1 Tripeptide Attenuates Surgery-Induced Neuroinflammation and Memory Deficits Through Regulation the NLRP3 Inflammasome

Cited by 15 publications

References 59 publications

The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders

The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders

Tat-NTS peptide protects neurons against cerebral ischemia-reperfusion injury via ANXA1 SUMOylation in microglia

Adiponectin Attenuates Splenectomy-Induced Cognitive Deficits by Neuroinflammation and Oxidative Stress via TLR4/MyD88/NF-κb Signaling Pathway in Aged Rats

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