Targeting neuroinflammation as a preventive and therapeutic approach for perioperative neurocognitive disorders

Cheng, Chi‐Hung; Wan, Hanxi; Cong, Peilin; Huang, Xinwei; Wu, Tingmei; He, Mengfan; Zhang, Qian; Xiong, Lize; Liang, Tian

doi:10.1186/s12974-022-02656-y

Cited by 25 publications

(6 citation statements)

References 194 publications

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“…Collectively, these results suggest that the mechanism by which Nanoligomer treatment improves cognitive function involves broadly reducing neuroinflammation. This idea is in agreement with our previous studies showing that Nanoligomer treatment reduces neuroinflammation and improves cognitive function in prion-disease mice (a model of severe neurodegeneration) [17], and with numerous other studies showing that targeting neuroinflammation improves cognitive function in mouse models of accelerated brain aging [71]. In future work, it will be important to identify the specific NF-κB/NLRP3-associated cytokine pathways that impact cognitive function most directly, as some cytokines (e.g., IL-10) can have both protective [72] and deleterious effects in the brain [73].…”

Section: Discussionsupporting

confidence: 93%

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Wahl,

Risen,

Osburn

et al. 2024

Preprint

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Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. Here, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old wildtype mice, and in a mouse model of tauopathy. We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and tauopathy mice. These effects of NF-κB/NLRP3-targeting Nanoligomer treatment were associated with reduced glial cell activation in old wildtype mice, less pathology in tauopathy mice, favorable changes in transcriptome signatures of inflammation (reduced) and neuronal health (increased) in both mouse models, and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting NF-κB/NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegenerative disease.

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Section: Discussionsupporting

confidence: 93%

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Wahl,

Risen,

Osburn

et al. 2024

Preprint

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“…The activation of glial cells in this transgenic mouse model is likely due to systemic inflammation as observed in other PND models [ 55 , 56 , 57 ]. Neuroinflammation is widely accepted as one of the important pathogenic mechanisms of PND [ 58 ]. Our Cbs knockout mice underwent the same procedure as other PND models did and it is very likely that our Cbs knockout mice developed neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

Middle aged CAMKII-Cre:<i>Cbs<sup>fl/fl</sup></i> mice: a new model for studying perioperative neurocognitive disorders

Li,

He,

Dai

et al. 2024

Exp. Anim.

Self Cite

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Postoperative complications, such as perioperative neurocognitive disorders (PND), have become a major issue affecting surgical outcomes. However, the mechanism of PND remains unclear, and stable animal models of middle-aged PND are lacking. S-adenosylmethionine (SAM), a cystathionine beta-synthase (CBS) allosteric activator, can reduce the level of plasma homocysteine and prevent the occurrence of PND. However, the time and resource-intensive process of constructing models of PND in elderly animals have limited progress in PND research and innovative therapy development. The present study aimed to construct a stable PND model in middle-aged CAMKII-Cre: Cbs fl/fl mice whose Cbs was specifically knocked out in CAMKII positive neurons. Behavioral tests showed that these middle-aged mice displayed cognitive deficits which were aggravated by exploratory laparotomy under isoflurane anesthesia. Compared with typical PND mice which were 18-month-old, these middle-aged mice showed similar cognitive deficits after undergoing exploratory laparotomy under isoflurane anesthesia. Though there was no significant difference in the number of neurons in either the hippocampus or the cortex, a significant increase in numbers of microglia and astrocytes in the hippocampus was observed. These indicate that middle-aged CAMKII-Cre: Cbs fl/fl mice can be used as a new PND model for mechanistic studies and therapy development for PND.

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“…Inflammation of the central nervous system is the main pathological process of PND ( 25 ). The surface of human intestinal mucosa is closely arranged by a layer of monolayer cells to form a barrier, preventing harmful substances from entering the blood circulation and protecting the health of the host.…”

Section: Gut Microbiota and Central Nervous Inflammatory Responsementioning

confidence: 99%

Gut microbiota in perioperative neurocognitive disorders: current evidence and future directions

2023

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Perioperative neurocognitive disorders (PND) is a common surgical anesthesia complication characterized by impairment of memory, attention, language understanding and social ability, which can lead to a decline in the quality of life of patients, prolong the hospitalization period and increase the mortality rate. PND has a high incidence rate, which has a great impact on postoperative recovery and quality of life of patients, and has caused a heavy economic burden to society and families. In recent years, PND has become an important public health problem. The high risk population of PND is more prone to gut microbiota imbalance, and gut microbiota may also affect the inflammatory response of the central nervous system through the microbiota-gut-brain axis. Meanwhile, Neuroinflammation and immune activation are important mechanisms of PND. Regulating gut microbiota through probiotics or fecal bacteria transplantation can significantly reduce neuroinflammation, reduce the abnormal activation of immune system and prevent the occurrence of PND. This review summarizes the research progress of gut microbiota and PND, providing basis for the prevention and treatment of PND.

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Targeting neuroinflammation as a preventive and therapeutic approach for perioperative neurocognitive disorders

Cited by 25 publications

References 194 publications

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Middle aged CAMKII-Cre:<i>Cbs<sup>fl/fl</sup></i> mice: a new model for studying perioperative neurocognitive disorders

Gut microbiota in perioperative neurocognitive disorders: current evidence and future directions

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