Saad Muhammad A E, Sayed Rabab Hamed, El-Sahar Ayman E, Sayed Noha H, Kortam Mona A, Fathy Nevine
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman, 4184, United Arab Emirates.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Clinical Pharmacy, School of Pharmacy, Newgiza University, Giza, Egypt.
Arch Biochem Biophys. 2025 Sep;771:110525. doi: 10.1016/j.abb.2025.110525. Epub 2025 Jun 29.
Binge drinking (BD) is heavy episodic alcohol drinking that is progressively practiced. Vast evidence verified that BD elicits neuronal and cognitive impairments. Debilitated autophagic machinery is a key culprit in BD-induced neurotoxicity. Palonosetron is a potent selective serotonin 5-HT3 receptor antagonist whose impact on BD has not yet been scrutinized. Thus, the present study aimed at exposing the potentiality of palonosetron and its link with AKT/mTOR/AMPK/ULK1 pathway in the BD-rat model. Rats were divided into 4 groups; group 1 received saline and Vanilla Ensure® Plus, whereas groups 2, 3 and 4 received 20 % w/v ethanol in Vanilla Ensure® Plus (intragastric gavage) every 8 h for 4 days, concomitantly with palonosetron (0.1 mg/kg, twice daily; i.p.) in groups 3 and 4, and chloroquine (50 mg/kg/day; i.p.) in group 4. BD impaired memory, locomotor, and cognitive functions, with concomitant TNF-α and IL-1β elevation implicating neuroinflammation-driven cognitive decline. The former effect was, mechanistically, triggered by halting autophagy via augmenting hippocampal pAKT/tAKT, pmTOR/tmTOR and pULK1/tULK1 ratios, while reducing pAMPK/tAMPK, with resultant imbalance of the autophagic markers; Beclin-1, LC3-II/LC3-I, p62 and caspase-3. Aberrant upregulation of miRNA-155 was also detected and was markedly correlated to AKT/mTOR/AMPK and autophagy trajectories. Palonosetron treatment significantly alleviated all the aforementioned deviations. Histopathological analysis further corroborated palonosetron neuroprotective effect. Chloroquine, a classical autophagy inhibitor, blunted palonosetron-induced improvement. The identified parameters were validated using the ShinyGO-0.81 database for functional enrichment analysis and KEGG pathway mapping. For the first time, palonosetron is likely to offer a reliable neuroprotective effect in BD via orchestrating the crosstalk between miRNA-155 and AKT/mTOR/AMPK signaling cascade.
暴饮（BD）是一种逐渐形成的重度间歇性饮酒行为。大量证据证实，暴饮会引发神经元和认知功能障碍。自噬机制受损是BD诱导神经毒性的关键因素。帕洛诺司琼是一种强效的选择性5-羟色胺5-HT3受体拮抗剂，其对BD的影响尚未得到研究。因此，本研究旨在揭示帕洛诺司琼在BD大鼠模型中的潜在作用及其与AKT/mTOR/AMPK/ULK1信号通路的联系。将大鼠分为4组；第1组给予生理盐水和香草味安素益加营养粉，而第2、3和4组每8小时经口灌胃给予含20%（w/v）乙醇的香草味安素益加营养粉，持续4天，第3和4组同时给予帕洛诺司琼（0.1mg/kg，每日两次；腹腔注射），第4组给予氯喹（50mg/kg/天；腹腔注射）。BD损害了记忆、运动和认知功能，同时TNF-α和IL-1β升高，提示神经炎症驱动认知功能下降。从机制上讲，前一种效应是通过增加海马pAKT/tAKT、pmTOR/tmTOR和pULK1/tULK1比值，同时降低pAMPK/tAMPK来阻断自噬而引发的，从而导致自噬标志物Beclin-1、LC3-II/LC3-I、p62和半胱天冬酶-3失衡。还检测到miRNA-155异常上调，且与AKT/mTOR/AMPK和自噬轨迹显著相关。帕洛诺司琼治疗显著减轻了上述所有异常情况。组织病理学分析进一步证实了帕洛诺司琼的神经保护作用。氯喹是一种经典的自噬抑制剂，减弱了帕洛诺司琼诱导的改善作用。使用ShinyGO-0.81数据库对确定的参数进行功能富集分析和KEGG通路映射验证。帕洛诺司琼首次可能通过协调miRNA-155与AKT/mTOR/AMPK信号级联之间的相互作用，在BD中提供可靠的神经保护作用。
