Nrf2 Ameliorates Sevoflurane-Induced Cognitive Deficits in Aged Mice by Inhibiting Neuroinflammation in the...

Perioperative neurocognitive disorders (PND), common complications that occur after anesthetized surgery in elderly patients, are major challenges to our rapidly growing aging population. The transcription factor known as nuclear factor erythroid-2-related factor 2 (Nrf2) is an essential component of the cellular antioxidant response, purportedly contributing to the preservation of cognitive functions such as learning and memory. Nevertheless, the function and intracellular processes involving Nrf2 in PND remain largely unknown. Therefore, we evaluate the influence and fundamental mechanism of Nrf2 on PND in aged mice. To establish the postoperative neurocognitive dysfunction (PND) model, aged mice were subjected to anesthesia via inhalation of 3% sevoflurane for a duration of 2 h. The role of Nrf2 in PND was investigated by administering microinjections of either the adeno-associated virus (AAV)-Nrf2 vector or a null virus vector into the hippocampal CA1 region of aged mice 28 days before exposure to sevoflurane. Various assays including enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and western blotting were employed to assess levels of pro-inflammatory cytokines, microglial activation, and the oxidative stress response. Furthermore, synaptic plasticity was evaluated through long-term potentiation (LTP) recording and Golgi staining techniques. Elevated expression of Nrf2 within the hippocampal CA1 region ameliorated sevoflurane-induced cognitive deficits, synaptic plasticity anomalies, and the oxidative stress reaction in aged mice. Furthermore, the activation of microglia and the release of pro-inflammatory cytokines (including IL-6, TNF-α, and IL-1β) within the hippocampus post-sevoflurane exposure were modulated in an Nrf2-dependent fashion. Based on the findings from present research, we conclude that Nrf2 ameliorates sevoflurane-induced cognitive dysfunction by inhibiting hippocampal neuroinflammation, thereby proposing a potential therapeutic target for PND.