Intranasal insulin administration affecting perioperative neurocognitive dysfunction by regulating calcium transport protein complex IP3R/GRP75/VDAC1 on MAMs

Perioperative neurocognitive disorders (PND) are common complications following surgery and anesthesia, especially in the elderly. These disorders are associated with disruptions in neuronal energy metabolism and mitochondrial function. This study explores the potential of intranasal insulin administration as a therapeutic strategy to prevent PND by targeting the calcium transport protein complex IP3R/GRP75/VDAC1 on mitochondria-associated endoplasmic reticulum membranes (MAMs). Male C57BL/6J mice underwent partial hepatectomy to induce PND and were subsequently treated with either intranasal insulin or saline. Cognitive function was evaluated using the Morris water maze test, and hippocampal tissue was analyzed for calcium transport protein complex IP3R/GRP75/VDAC1 expression and apoptosis markers. In vitro, HT22 and BV2 cell co-cultures were utilized to simulate surgical injury, with IP3R knockdown employed to assess its effects on oxidative stress and apoptosis. Intranasal insulin effectively alleviated cognitive impairment as demonstrated by improved performance in the Morris water maze. It significantly reduced neuronal apoptosis and modulated the expression of the IP3R/GRP75/VDAC1 complex, enhancing mitochondrial ATP production and stabilizing MAMs. Furthermore, insulin administration also increased PI3K/AKT signaling, counteracting the impact of surgical stress. In vitro experiments confirmed that IP3R knockdown mitigated inflammation-induced oxidative stress and neuronal apoptosis, while insulin's beneficial effects were blocked by inhibition of the PI3K/AKT pathway. Intranasal insulin mitigates PND by modulating the IP3R/GRP75/VDAC1 complex and enhancing mitochondrial function through the PI3K/AKT signaling pathway. This study supports the potential of intranasal insulin as a promising therapeutic strategy for preventing and managing PND, potentially leading to improved surgical outcomes for elderly patients. Insulin can reduce the overexpression of calcium transport protein complex IP3R/GRP75/VDAC1 induced by anesthesia and surgery by activating the PI3K/AKT signaling pathway, regulate the stability of MAMs and restore mitochondrial ATP production, thus reducing t neuron apoptosis. [Display omitted] •Intranasal insulin improves cognitive deficits induced by anesthesia and surgery in aged mice.•Intranasal insulin reduces neuronal apoptosis by regulating the IP3R/GRP75/VDAC1 complex, maintaining calcium balance, and preserving mitochondrial functio