Adiponectin attenuates splenectomy-induced cognitive deficits by alleviating neuroinflammation and oxidative stress via the TLR4/MyD88/NF-κb signaling pathway in aged rats

Abstract

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.

Long non‐coding RNA LncTUG1 regulates favourable compression force‐induced cementocytes mineralization via PU.1/TLR4/SphK1 signalling

“…An orthodontic closed coil spring (Grikin Advanced Materials, Beijing, China) was inserted between the maxillary left first molar (M1) and the incisor to achieve orthodontic molar movement with 0 g (Control group) and 25 g (Stress group). Stress was also combined with daily intraperitoneal injection of a TLR4‐specific agonist Lipopolysaccharide (LPS) (2 mg/kg, L2630, Millipore, Sigma‐Aldrich, St. Louis, MO, USA) 30 or with intraperitoneal injection of an SphK1 activator (0.05 mg/kg, K6PC‐5, Selleck, Beijing, China), 31 , 32 which were divided as Stress + LPS group and Stress + K6PC‐5 group, respectively. After 14 days, all experimental rats were euthanized by an overdose of pentobarbital and alveolar bone blocks that included M1 were harvested for further analysis.…”

Microglial exosome miR‐124‐3p in hippocampus alleviates cognitive impairment induced by postoperative pain in elderly mice

“…Surgical trauma induces the release of pro‐inflammatory cytokines and chemokines at the site of tissue injury, initiating a local inflammatory response. These inflammatory mediators can activate peripheral immune cells, such as macrophages and monocytes, which then infiltrate the CNS and further contribute to the neuroinflammatory cascade 10,11 . In the hippocampus, microglia, the resident immune cells of the brain, play a key role in sensing and responding to these inflammatory signals 12 .…”

“…These inflammatory mediators can activate peripheral immune cells, such as macrophages and monocytes, which then infiltrate the CNS and further contribute to the neuroinflammatory cascade. 10 , 11 In the hippocampus, microglia, the resident immune cells of the brain, play a key role in sensing and responding to these inflammatory signals. 12 Microglia activation is a complex process involving the transformation of microglia into an activated phenotype, characterized by morphological changes and the release of pro‐inflammatory cytokines, such as tumour necrosis factor α (TNF‐α) and interleukin‐1β (IL‐1β).…”