Tanshinone IIA mitigates postoperative cognitive dysfunction in aged rats by inhibiting hippocampal inflammation and ferroptosis: Role of Nrf2/SLC7A11/GPX4 axis activation

Abstract

Objective

Postoperative cognitive dysfunction (POCD) is a common and debilitating complication in elderly patients following surgery, leading to increased morbidity and reduced quality of life. This study aims to investigate the neuroprotective effects of Tanshinone IIA, a lipophilic compound derived from Salvia miltiorrhiza, in an aged rat model of POCD, and explore its underlying molecular mechanisms.

Methods

POCD model was established by a modified abdominal exploratory laparotomy. Rats were then intraperitoneally administered with Tanshinone IIA (10 mg/kg, 20 mg/kg, or 40 mg/kg) for 30 days. Cognitive functions were assessed using the morris water maze, novel object recognition test, and Y-maze test. Synaptic structures in the hippocampal CA1 region were examined by electron microscopy. Inflammatory and ferroptosis pathways were evaluated by measuring inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-4), nitric oxide synthase (iNOS) activity, lipid peroxidation products (malondialdehyde [MDA]; 4-hydroxy-2-nonenal [4-HNE]), Fe^2 + levels, and antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH]) using ELISA and commercial kits. mRNA and proteins levels were quantified by real-time quantitative polymerase chain reaction and western blot analysis.

Results

Tanshinone IIA significantly ameliorated cognitive deficits in aged POCD rats according to behavioral tests. It also restored synaptic ultrastructure in the hippocampal CA1 region and upregulated the expressions of synaptic proteins, including synapsin-1 and PSD-95. In addition, Tanshinone IIA effectively suppressed the hippocampal inflammatory pathway, as evidenced by the decreased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), an increased level of the anti-inflammatory cytokine IL-4, and the upregulation of the iNOS/NO pathway in the hippocampus. Furthermore, Tanshinone IIA mitigated ferroptosis by reducing MDA and 4-HNE contents, lowering Fe²⁺ level, and enhancing SOD activity and GSH level. Notably, Tanshinone IIA activated the Nrf2/SLC7A11/GPX4 axis in the hippocampus of aged POCD rats.

Conclusion

These findings suggest that Tanshinone IIA exerts neuroprotective effects in an aged rat model of POCD by attenuating hippocampal inflammation and ferroptosis, primarily through the activation of the Nrf2/SLC7A11/GPX4 axis.