Effects of anesthetic adjunctive agents on postoperative cognitive dysfunction in elderly patients undergoing noncardiac surgery: A Bayesian network meta-analysis.

BACKGROUND: Elderly patients are prone to postoperative cognitive dysfunction (POCD). The comparison of the effects of anesthetic adjuvant drugs on POCD in elderly patients undergoing noncardiac surgery remains controversial. METHODS: The final search took place on June 10, 2023. Randomized controlled trials including ketamine, ulinastatin, dexmedetomidine, parecoxib, and midazolam on the prevention and treatment of POCD in elderly undergoing noncardiac surgery were collected. A Bayesian network meta-analysis was performed to quantitatively combine the evidence. RESULTS: A total of 35 randomized trials were finally included in this systematic review, and the overall risk of bias is Allocation concealment. These anesthetic adjuvant drugs did not show significant differences in preventing POCD on postoperative days 1 and 7 compared with each other, but ulinastatin may be more effective in preventing POCD than dexmedetomidine [odds ratio (OR) = 0.28, 95% confidence interval (CI) = (0.10, 0.71)] and parecoxib [OR = 0.3, 95% CI = (0.10, 0.82 on postoperative day 3. The efficiency ranking results also find that ulinastatin and ketamine might provide better effects regarding POCD prevention. CONCLUSIONS: Ketamine and ulinastatin might have better effects in preventing POCD in elderly patients undergoing noncardiac surgery. Our meta-analysis provided evidence for the use of ulinastatin and ketamine in the prevention of POCD in elderly patients undergoing noncardiac surgery.

The BDNF-TrkB signaling pathway in the rostral anterior cingulate cortex is involved in the development of pain aversion in rats with bone cancer via NR2B and ERK-CREB signaling.

Patients with bone cancer pain (BCP) are more prone to aversion. which not only causes mental distress but also aggravates BCP. However, the mechanism of BCP-related aversion is still unclear. Previous studies have demonstrated that the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway of the rostral anterior cingulate cortex (rACC) plays an important role in the regulation of emotions related to chronic pain, such as neuropathic pain or inflammatory pain; however, few studies have investigated the role of this pathway in cancer pain. This study explored the role of BDNF in cancer pain-related aversion in the rACC and to determine whether N-methyl D-aspartate receptor subtype 2B (NR2B) and extracellular signal-regulated kinase (ERK)-cAMP response element-binding (CREB) signaling are involved in cancer pain-related aversion. A Sprague-Dawley rat model of BCP (one of the classic BCP models) was established, and the changes in pain aversion were detected by mechanical stimulation-induced conditioned place avoidance. Our findings confirmed that rats with BCP exhibited intense pain aversion accompanied by the up-regulated BDNF expression in the rACC. Additionally, the pain aversion of BCP rats was reduced while blocking the BDNF-TrkB. Furthermore, the expression of NR2B and phosphorylated ERK (pERK)/phosphorylated CREB (pCREB) were up-regulated with the development of pain aversion, whereas the use of NR2B blocker Ro25-6981, or ERK inhibitor U0126 could reduce the pain aversion. The expression of NR2B and pERK/pCREB were up-regulated after exogenous BDNF was injected into the rACC, whereas the expression levels of NR2B and pERK/pCREB were down-regulated after blocking the BDNF-TrkB signaling. In conclusion, the BDNF-TrkB signaling in the rACC mediates the generation of aversion in rats with BCP, which requires the involvement of NR2B and the ERK-CREB signaling pathway.

Inhibition of Adult Hippocampal Neurogenesis Plays a Role in Sevoflurane-Induced Cognitive Impairment in Aged Mice Through Brain-Derived Neurotrophic Factor/Tyrosine Receptor Kinase B and Neurotrophin-3/Tropomyosin Receptor Kinase C Pathways.

Sevoflurane anesthesia induces cognitive impairment, which may lead to perioperative neurocognitive disorders (PND). However, the factors and molecular mechanism underlying this impairment remains unclear. Adult hippocampal neurogenesis (AHN) in the subgranular zone of the hippocampus has been implicated in cognitive processes. Nonetheless, the direct role of AHN in sevoflurane-induced cognitive impairment has never been demonstrated. In this study, we explored the age and the concentration factors and the role of AHN inhibition in sevoflurane-induced cognitive impairment in sevoflurane inhalation model mice. We found that 3% sevoflurane exposure induced significant cognitive impairment and inhibition of AHN in aged mice but not adult mice. Expression of BDNF/TrkB and NT-3/TrkC was also decreased by 3% sevoflurane exposure in aged mice. Hippocampal brain-derived neurotrophic factor (BDNF) or Neurotrophin-3 (NT-3) microinjection could partially improve the sevoflurane-induced cognitive impairment and AHN inhibition, respectively. These results demonstrate that the cognitive impairment caused by sevoflurane inhalation is related to patient age and sevoflurane concentration. In conclusion, the molecular mechanism of cognitive impairment in the elderly is related to the inhibition of AHN through the BDNF/TrkB and NT-3/TrkC pathways. Thus, sevoflurane inhalation anesthesia may be safe for adult patients, but caution should be exercised when administering it to the elderly.

Dysfunction of inflammation-resolving pathways is associated with postoperative cognitive decline in elderly mice.

BACKGROUND: Postoperative cognitive dysfunction (POCD) refers to a reversible, perioperative mental disorder. POCD increases the likelihood of postoperative complications and the risk for postoperative mortality, typically among elderly patients (age 65 or older). The importance of the cholinergic anti-inflammatory pathway (CAP) in resolving neuro-inflammatory and cognitive decline caused by sterile trauma has been recognized. We speculate that the POCD in elderly mice is associated with dysfunction of CAP. METHODS: Mice were assigned to several groups (n = 5 in each group): AM (adult mice) Sham, AM (adult mice) Surgery, EM (elderly mice) Sham, EM (elderly mice) Surgery, and EMP (elderly mice with PNU) Surgery. At 24 h after surgery, assessed the cognitive levels. Pro-inflammatory cytokines in peripheral blood and splenic monocytes (TNF-α, IL-6 and IL-10) were assessed by ELISA and qPCR. Levels of M2 macrophages in hippocampus were visualized by immunofluorescence. Detecting CD11b/c+α7 nAChR+ cells in the spleens with flow cytometry. RESULTS: At postoperative 24 h, elderly mice exhibited significantly increased POCD compared with adult mice. The proinflammatory factor TNF-α and IL-6 were higher among elderly surgery mice (EM) compared with adult surgery (AM) and elderly-P surgery mice (EM-P); the anti-inflammatory factor IL-10 and M2 macrophages were lower among EM surgery mice compared with AM surgery and EM-P surgery mice. The CD11b/c+α7 nAChR+ population of splenocytes was reduced in the EM surgery mice. CONCLUSIONS: The exaggerated and persistent cognitive decline and inflammatory response among elderly mice were associated with dysfunction of CAP, and these phenomena were reversed by α7nAch receptor agonists.