Isoliensinine ameliorates postoperative neurocognitive disorder in aged mice by restoring hippocampal IGF-1 receptor signaling and suppressing oxidative stress and neuroinflammation

Postoperative neurocognitive disorder (PND) is a significant complication in elderly surgical patients, primarily driven by hippocampal neuroinflammation and oxidative stress. This study investigated the role of Insulin-like Growth Factor-1 Receptor (IGF1R) signaling in the pathogenesis of PND and evaluated the therapeutic potential of isoliensinine (ISL). Using a tibial surgery model in aged mice, we assessed cognitive function, hippocampal IGF-1/IGF1R pathway activity, and the effects of daily intraperitoneal ISL administration (5 or 10 mg/kg). Surgery induced significant cognitive deficits and anxiety-like behaviors, accompanied by a marked reduction in hippocampal IGF-1 protein levels and IGF1R phosphorylation, which were predominantly localized in neurons. Daily high-dose ISL administration effectively reversed these behavioral impairments and restored hippocampal IGF-1 expression and IGF1R phosphorylation. These neuroprotective effects were causally linked to IGF1R activation, as co-administration of the selective IGF1R inhibitor picropodophyllin (PPP) completely abolished ISL's therapeutic benefits. Mechanistically, ISL's effects were mediated by robust antioxidant and anti-inflammatory actions. ISL treatment reversed surgery-induced oxidative stress by promoting the nuclear translocation of NRF2 and restoring antioxidant defenses. Furthermore, ISL suppressed neuroinflammation by reducing hippocampal microglial activation and inhibiting the phosphorylation of p38 MAPK. Critically, these antioxidant and anti-inflammatory effects were also blocked by PPP. In conclusion, our findings demonstrate that ISL ameliorates PND by reactivating the neuronal IGF-1/IGF1R signaling pathway, which in turn suppresses downstream oxidative stress and microglial-driven neuroinflammation. This highlights ISL as a promising therapeutic candidate for the prevention and treatment of PND.