Yi Shanyong, Wei Lai, Zhao Bin, Yao Zhijun, Yang Bin
Xinxiang Key Laboratory of Forensic Toxicology, School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453002, Henan, China.
Henan Key Laboratory of Biological Psychiatry (Xinxiang Medical University), The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang 453002, Henan, China.
Curr Res Toxicol. 2024 Dec 21;8:100211. doi: 10.1016/j.crtox.2024.100211. eCollection 2025.
Exposure to alcohol can induce different degrees of damage to various tissues and organs, and brain is the most vulnerable part affected by alcohol. However, there is no detailed report on whether intermittent alcohol exposure can result in pathological changes in the hypothalamus of adolescent rats and the detailed mechanism. This study investigated pathological changes in the hypothalamus, probed the levels of inflammatory factors, and detected the expression of proteins related to endoplasmic reticulum stress (ERS) to determine whether ERS is involved in the injury process of the hypothalamus and the protective mechanism of L-3-n-butylphthalide (L-NBP). The results showed that intermittent alcohol exposure induced hypothalamic nerve injury, including cell apoptosis, increased the levels of inflammatory factors, and upregulated the expression of glucose-regulated protein 78 (GRP78), p-Inositol Requiring Enzyme 1α (p-IRE1α), apoptosis signal-regulating kinase 1 (ASK1), and p-c-Jun N-terminal kinase (p-JNK)). Tauroursodeoxycholic acid (TUDCA), an ERS inhibitor, significantly reduced the pathological damage described above. The increases in the levels of inflammatory factors, pathological injury, and increased levels of proteins associated with the IRE1α-ASK1-JNK pathway were alleviated by L-NBP. The present study indicated that intermittent alcohol exposure could lead to hypothalamic cell apoptosis in adolescent rats and L-NBP could alleviate the above injury by inhibiting the IRE1α-ASK1-JNK pathway. Abbreviations: Ang-2, Angiopoietin-2; ASK1, Apoptosis signal-regulating kinase 1; ER, Endoplasmic reticulum; ERS, Endoplasmic reticulum stress; ELISA, Enzyme-linked immunosorbent assay; GFAP, Glial fibrillary acidic protein; GRP78, Glucose-regulated protein 78; IBA1, Ionized calcium binding adapter molecule 1; i.p., Intraperitoneal; IRE1α, Inositol Requiring Enzyme 1α; JNK, c-Jun N-terminal kinase; L-NBP, L-3-n-butylphthalide; PND, Postnatal day; PVDF, Polyvinylidene difluoride; SDS-PAGE, Sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TRAF2, TNF-receptor associated factor 2; TUDCA, Tauroursodeoxycholic acid; VEGF, Vascular endothelial growth factor.
接触酒精会对各种组织和器官造成不同程度的损害，而大脑是受酒精影响最脆弱的部位。然而，关于间歇性酒精暴露是否会导致青春期大鼠下丘脑发生病理变化及其详细机制，目前尚无详细报道。本研究调查了下丘脑的病理变化，探究了炎症因子水平，并检测了与内质网应激（ERS）相关的蛋白质表达，以确定ERS是否参与下丘脑的损伤过程以及L-3-正丁基苯酞（L-NBP）的保护机制。结果表明，间歇性酒精暴露可导致下丘脑神经损伤，包括细胞凋亡，炎症因子水平升高，葡萄糖调节蛋白78（GRP78）、磷酸化肌醇需要酶1α（p-IRE1α）、凋亡信号调节激酶1（ASK1）和磷酸化c-Jun氨基末端激酶（p-JNK）的表达上调。ERS抑制剂牛磺熊去氧胆酸（TUDCA）显著减轻了上述病理损伤。L-NBP减轻了炎症因子水平的升高、病理损伤以及与IRE1α-ASK1-JNK通路相关蛋白质水平的升高。本研究表明，间歇性酒精暴露可导致青春期大鼠下丘脑细胞凋亡，而L-NBP可通过抑制IRE1α-ASK1-JNK通路减轻上述损伤。缩写：Ang-2，血管生成素-2；ASK1，凋亡信号调节激酶1；ER，内质网；ERS，内质网应激；ELISA，酶联免疫吸附测定；GFAP，胶质纤维酸性蛋白；GRP78，葡萄糖调节蛋白78；IBA1，离子钙结合衔接分子1；i.p.，腹腔注射；IRE1α，肌醇需要酶1α；JNK，c-Jun氨基末端激酶；L-NBP，L-3-正丁基苯酞；PND，出生后天数；PVDF，聚偏二氟乙烯；SDS-PAGE，十二烷基硫酸钠-聚丙烯酰胺凝胶电泳；TRAF2，肿瘤坏死因子受体相关因子2；TUDCA，牛磺熊去氧胆酸；VEGF，血管内皮生长因子。
