Potential mechanism of Taohong Siwu Decoction in preventing and treating postoperative delirium in intertrochanteric fracture patients based on retrospective analysis and network pharmacology

Abstract

Objective: Elderly patients with hip fractures are at a greater risk of developing postoperative delirium (POD), which significantly impacts their recovery and overall quality of life. Neuroinflammation is a pathogenic mechanism of POD. Taohong Siwu Decoction (THSWD), known for its ability to promote blood circulation and remove blood stasis, can effectively reduce inflammation in the nervous system. Therefore, the objective of this article is to provide a comprehensive summary of the clinical efficacy of THSWD in the prevention of POD. Additionally, it aims to investigate the underlying mechanism of THSWD in the prevention and treatment of POD using network pharmacology and molecular docking.

Methods: We conducted a retrospective analysis of patients with intertrochanteric fractures between January 2016 and October 2021. The patients were divided into two groups: the control and THSWD group. We performed a comparative analysis of hemoglobin (HB), albumin (ALB), C-reactive protein (CRP), blood urea nitrogen (BUN), and the blood urea nitrogen to creatinine ratio (BCR) on two different time points: the day before surgery (D0) and the third day after surgery (D3). Furthermore, we examined the incidence and duration of delirium, as well as the Harris Hip Score (HHS) at 3 months and 12 months post-surgery. Network pharmacology was employed to identify the primary targets and mechanisms of THSWD in the management of delirium. Molecular docking was employed to confirm the interaction between active ingredients and COX-2. Inflammatory cytokines, including cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor- (TNF-α), were measured using the enzyme-linked immunosorbent assay (ELISA). The cognitive status of the patients was assessed using the Mini-Mental State Examination (MMSE) scoring system.

Results: Regardless of whether it is in D0 or D3, THSWD treatment can increase HB levels while decreasing BCR. In D3, the THSWD group demonstrated a significant reduction in the expression of CRP and BUN when compared to the control group. However, there were no significant differences in ABL levels, surgery duration, and blood loss between the two groups. Additionally, THSWD treatment requires fewer blood transfusions and can reduce the incidence and duration of POD. The results of the logistic analysis suggest that both CRP levels and BCR independently contribute to the risk of POD. Network pharmacology analysis indicates that THSWD has the potential to prevent and treat POD possibly through inflammatory pathways such as IL-17 signaling pathways and NF-kappa B signaling pathways. Molecular docking validated the interaction between the active ingredient of THSWD and COX-2. Furthermore, THSWD treatment can reduce the levels of COX-2, IL-1β, IL-6, TNF-α, BUN and CRP in the blood of patients with POD, increase HB levels, and enhance MMSE scores. The expression of COX-2 is positively associated with other inflammatory markers (IL-1β, IL-6, TNF-α, and CRP), and inversely associated with MMSE.

Conclusion: THSWD has been found to have a preventive and therapeutic effect on POD in intertrochanteric fracture patients possibly through inflammatory pathways. This effect may be attributed to its ability to increase hemoglobin levels and reduce the levels of certain detrimental factors, such as blood urea nitrogen and inflammatory factors.

Keywords: Inflammation; Intertrochanteric fractures; Postoperative delirium; Taohong Siwu Decoction.

Fig. 1

Study flow chart

Fig. 2

THSWD increased hemoglobin levels and reduced levels of urea nitrogen and C-reactive protein. a-e Expression levels of hemoglobin (HB), C-reactive protein (CRP), blood urea nitrogen (BUN), serum albumin (ALB), and blood creatinine (CREA) in the blood were measured on the day before surgery (D0) and the third day after surgery (D3). f The blood urea nitrogen to creatinine ratio (BCR)

Fig. 3

THSWD could lower the likelihood of POD and shorten its duration. a Surgical duration b Blood loss c Transfusion volume d Postoperative delirium incidence rate e Delirium onset duration after surgery f Delirium duration after surgery g Harris Hip Score (HHS) at 3 and 12 months after surgery. h The forest plot illustrates the hazard ratios of different factors along with their corresponding confidence intervals

Fig. 4

Building a protein-protein interaction network and investigating potential pathways for the prevention and treatment of delirium by THSWD a Overlaps between THSWD targets and targets in delirium. b PPI network involving THSWD and delirium-related targets. c-e GO enrichment analysis. f Enrichment analysis of KEGG pathways

Fig. 5

Target network and molecular docking of THSWD’s active ingredients for delirium. a Chinese medicine-active ingredient-target network b The top ten active ingredients based on their degree value c The top ten targets based on their degree value d-g Molecular docking revealed the binding of baicalein, hederagenin, senkyunone and kaempferol to the COX-2 protein(blue)

Fig. 6

THSWD could downregulate the expression of inflammatory factors in the blood of patients with POD a The levels of COX-2 IL-1β, IL-6, and TNF-α were detected using ELISA on both the day of delirium onset (D1) and the 5th day after delirium onset. n = 6.b-d Expression levels of BUN, CRP, and HB in the blood were measured. e MMSE (Mini-Mental State Examination) scores f Heat map illustrating the correlation among different indicators