Background 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 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. Methods Eighteen 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 + LPS (i.p. administration of 2 mg/kg LPS). The cognitive function of the rats was assessed with the Morris water maze (MWM) test. Immunohistochemistry/ immunofluorescence, western blotting and ELISA were used to evaluate the activation of the TLR4/NF-κb axis, oxidative stress-mediated apoptosis, microglial activation and proinflammatory cytokine expression in the hippocampus. Results We first found that APN treatment significantly improved learning and cognitive function in the MWM test after surgical trauma. Further experiments showed that APN could inhibit the TLR4/MyD88/NF-κb p65 pathway to decrease the degree of oxidative damage (MDA, SOD and caspase 3) and microglia-mediated neuroinflammation (IBA1, TNF-α, IL-1β and IL-6). The TLR4 antagonist TAK-242 had a similar effect as APN, while the TLR4 agonist LPS abolished the beneficial effect of APN. Conclusions APN exerts a neuroprotective effect against cognitive deficits induced by peripheral trauma, and the possible mechanisms include inhibition of oxidative stress and neuroinflammation, which is mediated by suppression of the TLR4/MyD88/NF-κb signaling pathway. We propose that APN is a promising candidate for PND treatment.

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.

Objective To evaluate the efficacy and safety of remimazolam mesylate for general anesthesia in elderly patients. Methods Patents aged 60 to 80 years who were scheduled to undergo surgery were randomized into three groups: Group A (remimazolam mesylate 6 mg/kg/h), Group B (remimazolam mesylate 12 mg/kg/h), or Group C (propofol 2.0-2.5 mg/kg). Primary efficacy indicators (success rate of anesthesia sedation), secondary efficacy indicators (BIS value, anesthesia induction time, anesthesia awakening time), safety efficacy indicators (incidence of anesthetic hypotension; incidence of anesthetic hypoxemia) and incidence of adverse events (intravenous pain, nausea and vomiting, etc.) were routinely monitored. Results The success rate of anesthesia sedation was 95% in the 6 mg/kg/h remimazolam mesylate group and 100% in the 12 mg/kg/h remimazolam mesylate and propofol groups. Noninferiority of remimazolam mesylate [95% confidence interval (0.04; 0.047)]. There were statistically significant differences in anesthesia awakening time, use of norepinephrine, and adverse events (P < 0.05). There were no significant differences in the time of anesthesia induction or incidence of bradycardia and hypotension among the three groups. However, compared with the propofol group, the awakening time in the remimazolam tosylate groups was significantly shorter (P < 0.05), the effect on heart rate was lower, and there was no pain from intravenous injection. The intraoperative BIS values of the three groups were all maintained at 40–63, and no intraoperative awareness was found. At the same time, the use of norepinephrine in the remimazolam tosylate groups was significantly reduced (P < 0.05). Conclusions Remimazolam mesylate is well tolerated and noninferior to propofol with regard to efficacy as a sedative hypnotic for general anesthesia. Remimazolam mesylate can accelerate recovery from anesthesia, have less impact on heart rate, and decrease the use of vasoactive drugs and intravenous pain. Clinical trial registration: This study was approved by the Clinical Trials Ethics Committee of Dongguan People's Hospital (KYKT2020-054), and registered at http://www.chictr.org.cn (11/06/2021, ChiCTR2100047274). The study protocol followed the CONSORT guidelines. The study protocol was performed in the relevant guidelines.