Pleiotropic role of mGluR7/MAPK signaling in the protection of intelectin-1 against cerebral ischemia-reperfusion injury

作者：Xiaochen Niu, Bodong Wang, Aizhen Zhao, Wenwen Yang, Ning Li, Wenzhen Shi, Wangrui Lei, Ying Cheng, Baoying Wang, Yang Yang, Songdi Wu, Ye Tian · 发表于：Pharmacological Research · 年份：2025 · DOI：10.1016/j.phrs.2025.107735 · 被引用次数：6 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、S100 Proteins and Annexins、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Acute ischemic stroke (AIS) is a serious neurological condition with limited treatment options available. Studies have shown that levels of the protein intelectin-1 (ITLN-1) are linked to stroke severity and poor neurological outcomes. This study aimed to evaluate the role and molecular mechanisms of ITLN-1 in AIS. This study found that ITLN-1 is widely expressed in various brain regions, while ITLN-1 levels were significantly decreased in the blood and brain tissues of ischemic stroke patients. ITLN-1 overexpression reduced neuronal damage and motor deficits in transient middle cerebral artery occlusion/reperfusion (tMCAO/R) treated mice. Treatment with Rh-omentin or ITLN-1 overexpression also had a protective effect in cellular injury models. RNA-seq analysis revealed that ITLN-1 impacts specific genes and pathways, particularly those related to mGluR7. Molecular docking and CO-IP analysis confirmed that ITLN-1 directly binds to and interacts with mGluR7. The study also showed that the ITLN-1/mGluR7 axis regulates MAPK cascades (ERK and p38) to reduce cerebral oxidative stress, mitochondrial dysfunction, and cell death. Additionally, the compound AKR-501 was found to have a protective effect against cerebral ischemia by modulating the ITLN-1/mGluR7/MAPK cascades. Overall, these findings suggest that targeting ITLN-1 could be a promising therapeutic approach for managing AIS, with important clinical implications.