Intranasal Insulin Administration Affecting Perioperative Neurocognitive Dysfunction by Regulating Calcium Transport Protein Complex IP3R/GRP75/VDAC1 on MAMs

Huiqin Liu; Yanhua Jiang; Lianhui Cong; Xinyue Zhang; Yongjian Zhou; Pan Xue; Sidan Liu; Renyi Wang; Xuezhao Cao

doi:10.1016/j.freeradbiomed.2025.01.006

Intranasal Insulin Administration Affecting Perioperative Neurocognitive Dysfunction by Regulating Calcium Transport Protein Complex IP3R/GRP75/VDAC1 on MAMs

Free Radic Biol Med. 2025 Jan 4:S0891-5849(25)00006-1. doi: 10.1016/j.freeradbiomed.2025.01.006. Online ahead of print.

Authors

Huiqin Liu¹, Yanhua Jiang¹, Lianhui Cong¹, Xinyue Zhang¹, Yongjian Zhou¹, Pan Xue¹, Sidan Liu¹, Renyi Wang¹, Xuezhao Cao²

Affiliations

¹ Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, China.
² Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, China. Electronic address: [email protected].

PMID: 39761768
DOI: 10.1016/j.freeradbiomed.2025.01.006

Abstract

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).

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Calcium transport protein complex; Intranasal insulin; Mitochondria-associated ER membranes; Mitochondrial dysfunction; Perioperative neurocognitive disorders.