<scp>PGE</scp>2‐<scp>EP</scp>3 signaling exacerbates hippocampus‐dependent cognitive impairment after laparotomy by reducing expression levels of hippocampal synaptic plasticity‐related proteins in aged mice

Xiao, Jingyu; Xiong, Bingrui; Zhang, Wen; Zhou, Wenchang; Yang, Hui; Gao, Feng; Xiang, Hongyu; Manyande, Anne; Tian, Xiaojing; Tian, Yuan

doi:10.1111/cns.12832

Cited by 45 publications

(30 citation statements)

References 62 publications

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“…The level of synaptophysin (SYP), a synaptic protein correlated with cognitive function, was also markedly reduced at 72 hours after surgery. These data are consistent with the findings from a previous study that peripheral surgery leads to an exaggerated neuroinflammatory response in aged mice . These data also support the clinical observation that senior patients are more vulnerable to develop POD and POCD …”

Section: Discussionsupporting

confidence: 92%

“…These data are consistent with the findings from a previous study that peripheral surgery leads to an exaggerated neuroinflammatory response in aged mice. 6,7 These data also support the clinical observation that senior patients are more vulnerable to develop POD and POCD. 3,24 Several studies indicate that exaggerated cytokine production in the aged brain following central or peripheral stimulation is dependent on activation of microglia.…”

Section: Discussionsupporting

confidence: 77%

“…3,4 In animal models of peripheral surgical intervention (tibial fracture, open abdominal surgery, etc), aged animals exhibit worsened cognitive outcome, and this deterioration is linked to exacerbated neuroinflammation and macrophage/microglial activation in the aged brain. [5][6][7][8] Despite these observations, little is known about the mechanisms involved in age-related pathology following peripheral surgical intervention.…”

Section: Introductionmentioning

confidence: 99%

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Aging alters Hv1‐mediated microglial polarization and enhances neuroinflammation after peripheral surgery

et al. 2019

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Perioperative neurocognitive disorders have been widely recognized as common adverse events after surgical intervention. Aging is one of the most important independent risk factors for worsened cognitive outcome, and this deterioration is linked to exacerbated microglia‐mediated neuroinflammation in the aged brain. Under pathological stimulation, microglia are capable of polarizing toward proinflammatory M1 and anti‐inflammatory M2 phenotypes. In the present study, we examined how aging affects microglial responses and neuroinflammation following peripheral surgery. Adult (2‐3 months) and aged (18 months old) male C57/BL6 mice were subjected to tibial fracture or sham surgery. Aged mice exhibited higher level of tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) in the hippocampus. The expression of synaptic protein synaptophysin (SYP) was also markedly reduced in the aged brain after the surgery. Both adult and aged mice showed significant increases in M1 microglial polarization (CD16/32). In contrast, tibial fracture surgery induced a decreased M2 microglial polarization (CD206, Ym1/2, Arg1) in aged brain but enhanced M2 microglial polarization in adult brain. Aged mice have upregulated voltage‐gated proton channel (Hv1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit expression compared with adult mice. The percentage of CD16/32‐positive M1 microglia colabeling with Hv1 was higher in aged mice after tibial fracture surgery. Thus, Hv1/NADPH oxidase upregulation in the aged brain may shift the dynamic equilibrium of microglial activation toward M1 polarization and exaggerate postoperative neuroinflammatory responses after peripheral surgical intervention.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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Aging alters Hv1‐mediated microglial polarization and enhances neuroinflammation after peripheral surgery

et al. 2019

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“…Fear condition test (FCT) was performed as previously reported 3 . Briefly, after mice accommodated to the condition, one tone‐foot‐shock pairing was given (tone, 30 seconds, 70 dB, 1 kHz; foot‐shock, 2 seconds, 0.5 mA, a 30‐second interval after the shock).…”

Section: Methodsmentioning

confidence: 99%

Disruption of the GABAergic system contributes to the development of perioperative neurocognitive disorders after anesthesia and surgery in aged mice

et al. 2020

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Aims Perioperative neurocognitive disorders (PND) are associated with cognitive impairment in the preoperative or postoperative period, and neuroinflammation is thought to be the most important mechanisms especially during the postoperative period. The GABAergic system is easily disrupted by neuroinflammation. This study investigated the impact of the GABAergic system on PND after anesthesia and surgery. Methods An animal model of laparotomy with inhalation anesthesia in 16‐month‐old mice was addressed. Effects of the GABAergic system were assessed using biochemical analysis. Pharmacological blocking of α5GABAARs or P38 mitogen‐activated protein kinase (MAPK) were applied to investigate the effects of the GABAergic system. Results After laparotomy, the hippocampus‐dependent memory and long‐term potentiation were impaired, the levels of IL‐6, IL‐1β and TNF‐α up‐regulated in the hippocampus, the concentration of GABA decreased, and the protein levels of the surface α5GABAARs up‐regulated. Pharmacological blocking of α5GABAARs with L655,708 alleviated laparotomy induced cognitive deficits. Further studies found that the P38 MAPK signaling pathway was involved and pharmacological blocking with SB203,580 alleviated memory dysfunctions. Conclusions Anesthesia and surgery caused neuroinflammation in the hippocampus, which consequently disrupted the GABAergic system, increased the expressions of surface α5GABAARs especially through the P38 MAPK signaling pathway, and eventually led to hippocampus‐dependent memory dysfunctions.

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“…These changes in protein levels, as well as cognitive impairments, could be attenuated by the pharmacological blockade or the genetic suppression of the inflammatory prostaglandin E2 pathway. Therefore, neuroinflammation is thought to be an upstream event of the synaptic changes observed during POCD [60].…”

Section: Improvement Of Synaptic Plasticitymentioning

confidence: 99%

Application of Acupuncture to Attenuate Immune Responses and Oxidative Stress in Postoperative Cognitive Dysfunction: What Do We Know So Far?

Zhao

Yeung

et al. 2020

Oxidative Medicine and Cellular Longevity

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Postoperative cognitive dysfunction (POCD) is a common sequela following surgery and hospitalization. The prevention and management of POCD are important during clinical practice. POCD more commonly affects elderly patients who have undergone major surgery and can result in major decline in quality of life for both patients and their families. Acupuncture has been suggested as an effective intervention for many neurological disorders. In recent years, there are increasing interest in the use of acupuncture to prevent and treat POCD. In this review, we summarized the clinical and preclinical evidence of acupuncture on POCD using a narrative approach and discussed the potential mechanisms involved. The experimental details and findings of studies were summarized in tables and analyzed. Most of the clinical studies suggested that acupuncture before surgery could reduce the incidence of POCD and reduce the levels of systematic inflammatory markers. However, their reliability is limited by methodological flaws. Animal studies showed that acupuncture reduced cognitive impairment and the associated pathology after various types of surgery. It is possible that acupuncture modulates inflammation, oxidative stress, synaptic changes, and other cellular events to mitigate POCD. In conclusion, acupuncture is a potential intervention for POCD. More clinical studies with good research design are required to confirm its effectiveness. At the same time, findings from animal studies will help reveal the protective mechanisms, in which systematic inflammation is likely to play a major role.

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PGE2‐EP3 signaling exacerbates hippocampus‐dependent cognitive impairment after laparotomy by reducing expression levels of hippocampal synaptic plasticity‐related proteins in aged mice

Abstract: This study showed that PGE2-EP3 signaling pathway was involved in the progression of POCD and identified EP3 receptor as a promising treatment target.

Cited by 45 publications

References 62 publications

Aging alters Hv1‐mediated microglial polarization and enhances neuroinflammation after peripheral surgery

Aging alters Hv1‐mediated microglial polarization and enhances neuroinflammation after peripheral surgery

Disruption of the GABAergic system contributes to the development of perioperative neurocognitive disorders after anesthesia and surgery in aged mice

Application of Acupuncture to Attenuate Immune Responses and Oxidative Stress in Postoperative Cognitive Dysfunction: What Do We Know So Far?

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