The Oral Pretreatment of Glycyrrhizin Prevents Surgery-Induced Cognitive Impairment in Aged Mice by Reducing Neuroinflammation and Alzheimer's-Related Pathology via HMGB1 Inhibition.

Neuroinflammation and Alzheimer's-related pathology play essential roles in postoperative cognitive dysfunction (POCD). High-mobility group box 1 (HMGB1) is well known as a pivotal mediator in neuroinflammation, and its associations with Alzheimer's-related pathology and POCD have been also revealed. Glycyrrhizin is a nature inhibitor of HMGB1 and is reported with neuroprotective effects through oral administration. Therefore, the present study aims to test the hypothesis that the oral pretreatment of glycyrrhizin prevents POCD by inhibiting HMGB1-induced neuroinflammation and Alzheimer's-related pathology in aged mice. Aged male C57BL/6 mice were subjected to the splenectomy surgery under general anesthesia and the oral pretreatment of glycyrrhizin. The postoperative cognitive changes were evaluated by using Morris water maze (MWM) test. The protein expressions of HMGB1, TLR4, NF-κB, p-Tau, and pro-inflammatory cytokines were determined by Western blot assay. The hippocampal level of β-amyloid (Aβ) was assessed by ELISA assay. We found that the oral pretreatment of glycyrrhizin inhibited HMGB1 cytosolic expression, increased the PSD-95 protein expression, and attenuated the severity of postoperative memory impairment, as indicated by the shorter swimming latency and distance in MWM trials when compared with the mice subjected to the surgery alone. Additionally, the pretreatment of glycyrrhizin reduced the postoperative neuroinflammation (production of pro-inflammatory cytokines including IL-1β, TNF-α, and IL-6 as well as NF-κB nuclear expression) and Alzheimer's-related pathology (Tau phosphorylation at the site of AT-8 and Ser396 as well as Aβ40 and 42 concentrations) in the hippocampus of the aged mice undergoing splenectomy surgery. In conclusion, our results suggest that the oral pretreatment of glycyrrhizin can prevent the postoperative cognitive impairment by reducing neuroinflammation and Alzheimer's-related pathology in the hippocampus of aged mice via HMGB1 inhibition.