Dexmedetomidine attenuates perioperative neurocognitive disorders by suppressing hippocampal neuroinflammation and HMGB1/RAGE/NF-κB signaling pathway

Wang, Jinxu; Xin, Yueyang; Chu, Tiantian; Liu, Cheng; Xu, Aiguo

doi:10.1016/j.biopha.2022.113006

Cited by 22 publications

(9 citation statements)

References 56 publications

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“…In our study, Cbs was knocked out in neurons, not in microglia. 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 ].…”

Section: Discussionmentioning

confidence: 86%

Middle aged CAMKII-Cre:Cbsfl/fl mice: a new model for studying perioperative neurocognitive disorders

Li,

He,

Dai

et al. 2024

Exp. Anim.

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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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Section: Discussionmentioning

confidence: 86%

Middle aged CAMKII-Cre:Cbsfl/fl mice: a new model for studying perioperative neurocognitive disorders

Li,

He,

Dai

et al. 2024

Exp. Anim.

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“…Dexmedetomidine reduces neuroinflammation in lipopolysaccharide-treated BV2 cells by reversing microglial M1/M2 polarization [ 30 ]. Dexmedetomidine ameliorates perioperative neurocognitive disorders via regulation of M1/M2 polarization [ 69 ]. Additionally, dexmedetomidine promotes M2-polarization of microglia and thus protects against ischemic brain injury [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine alleviates blood-brain barrier disruption in rats after cerebral ischemia-reperfusion by suppressing JNK and p38 MAPK signaling

Zhu,

Wang,

Chang

et al. 2024

Korean J Physiol Pharmacol

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Dexmedetomidine displays multiple mechanisms of neuroprotection in ameliorating ischemic brain injury. In this study, we explored the beneficial effects of dexmedetomidine on blood-brain barrier (BBB) integrity and neuroinflammation in cerebral ischemia/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h and reperfusion for 24 h to establish a rat model of cerebral ischemia/reperfusion injury. Dexmedetomidine (9 μg/kg) was administered to rats 30 min after MCAO through intravenous injection, and SB203580 (a p38 MAPK inhibitor, 200 μg/kg) was injected intraperitoneally 30 min before MCAO. Brain damages were evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, Nissl staining, and brain water content assessment. BBB permeability was examined by Evans blue staining. Expression levels of claudin-5, zonula occludens-1, occludin, and matrix metalloproteinase-9 (MMP-9) as well as M1/M2 phenotypes-associated markers were assessed using immunofluorescence, RT-qPCR, Western blotting, and gelatin zymography. Enzyme-linked immunosorbent assay was used to examine inflammatory cytokine levels. We found that dexmedetomidine or SB203580 attenuated infarct volume, brain edema, BBB permeability, and neuroinflammation, and promoted M2 microglial polarization after cerebral ischemia/reperfusion injury. Increased MMP-9 activity by ischemia/reperfusion injury was inhibited by dexmedetomidine or SB203580. Dexmedetomidine inhibited the activation of the ERK, JNK, and p38 MAPK pathways. Moreover, activation of JNK or p38 MAPK reversed the protective effects of dexmedetomidine against ischemic brain injury. Overall, dexmedetomidine ameliorated brain injury by alleviating BBB permeability and promoting M2 polarization in experimental cerebral ischemia/reperfusion injury model by inhibiting the activation of JNK and p38 MAPK pathways.

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“…This finding does not support the proposition that dexmedetomidine reduces delirium and postoperative cognitive dysfunction after cardiac surgery via a reduction in neuroinflammation. While studies in murine models have been supportive of this concept [37], direct immunohistochemical evidence of microglial activation following cardiac surgery is understandably lacking in humans. To our knowledge, this is the first trial to examine this question in a clinically relevant large animal model of CPB and to examine microglial morphometric activation directly rather than relying on increased plasma levels of neuroinflammatory biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Effects of dexmedetomidine on kidney and brain tissue microcirculation and histology in ovine cardiopulmonary bypass: a randomised controlled trial

Jufar,

May,

Booth

et al. 2023

Anaesthesia

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SummaryCardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra‐operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α2‐agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4–0.8 μg.kg‐1.h‐1) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24–7.23) to 1.56 (0.84–2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33–7.07) to 1.51 (0.33–2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi‐quantitative scale (0–3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1–2 [0–3]) vs. 0 (0–0.3 [0–1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass.

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Dexmedetomidine attenuates perioperative neurocognitive disorders by suppressing hippocampal neuroinflammation and HMGB1/RAGE/NF-κB signaling pathway

Cited by 22 publications

References 56 publications

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

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

Dexmedetomidine alleviates blood-brain barrier disruption in rats after cerebral ischemia-reperfusion by suppressing JNK and p38 MAPK signaling

Effects of dexmedetomidine on kidney and brain tissue microcirculation and histology in ovine cardiopulmonary bypass: a randomised controlled trial

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