Our findings highlight that treatment with DMED during, but not after, peripheral SI can prevent subsequent hippocampal neuroinflammation, overexpression of TLR-4 in microglia, and cognitive dysfunction, as mediated by the α-AR signaling pathway.
Our findings indicate that surgery-induced acute, transient, brain-wide neuroinflammation may be involved in the pathogenesis of the postoperative delirium-like cognitive deficits in rats. Furthermore, neuroinflammation may convert from acute to chronic in an age- and hippocampal-specific manner, likely resulting in the development of sustained cognitive dysfunction.
The maladaptive response of aged microglia to surgery and consequent neuroinflammation plays a key pathogenic role in postoperative cognitive dysfunction (POCD). Here, we assessed the preventive effect of resveratrol (RESV) for POCD in aged rats. The emulsified form of RESV (e-RESV) was selected to improve its oral and brain bioavailability. Animals were assigned to one of four groups: e-RESV (80 mg/kg) versus vehicle treatment by abdominal surgery versus isoflurane anesthesia alone (n = 8 in each group). The dose-dependent effects of e-RESV were also assessed in dose range of 0-60 mg/kg. Either vehicle or e-RESV was administered intragastrically 24 h before surgery. Seven days after procedure, cognitive function was evaluated using a novel object recognition test, followed by measurement of hippocampal pro-inflammatory cytokine levels. Our results showed that pre-treatment with e-RESV attenuated the surgery-induced cognitive impairment and related hippocampal neuroinflammation at 40 mg/kg or higher doses. Additionally, the ex-vivo experiments revealed that the preemptive e-RESV regimen reduced the hippocampal microglial immune reactivity to lipopolysaccharide. Furthermore, e-RESV induced neuroprotective benefits were inhibited by the concomitant administration of sirtinol, a specific SIRT1 inhibitor. Our findings imply the preventive potential of e-RESV for POCD via the SIRT1 signaling pathway.
Systemic inflammation can trigger transient or longer-lasting cognitive impairments, particularly in elderly patients. However, its pathogenesis has not been sufficiently clarified. In this study, we explored the potential effects of multisensory rehabilitation on cognitive dysfunction following systemic inflammation using an animal model. Aged male Wister rats were randomly injected intraperitoneally with either saline (control) or lipopolysaccharide (LPS; 5 mg/kg). After injection, both groups of rats were randomly assigned to either of two housing conditions (n = 8 in each condition): a standard cage environment (SC group) or a multisensory early rehabilitation environment (ER group). Cognitive function was examined after 7 days in the assigned environmental condition using a novel object recognition test. In the SC group, the LPS-treated rats showed impaired cognitive function compared with the control animals. These memory deficits were positively correlated with the levels of both tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the hippocampus. On the other hand, in the LPS-treated ER group, neither cognitive impairment nor an increase in hippocampal levels of both TNF-α and IL-1β was found. These results imply that early rehabilitation (ER) intervention may be effective in preventing cognitive dysfunction following systemic inflammation via its anti-neuroinflammatory effects.
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