Islam Md Torequl, Hasan Md Sakib Al, Mia Emon, Ansari Irfan Aamer, Ansari Siddique Akber, Islam Md Amirul, Saifuzzaman Md
Pharmacy Discipline, Khulna University, Khulna, Bangladesh.
Department of Pharmacy, Gopalganj Science and Technology University, Gopalganj, Bangladesh.
Brain Behav. 2025 Mar;15(3):e70446. doi: 10.1002/brb3.70446.
Citronellal (CTL), a monoterpenoid, exhibits notable neurological activity, including anxiolytic, and anticonvulsant effects, primarily through GABAergic pathways. Our current study aimed to explore CTL's sedative potential using in vitro, in vivo, and in silico approaches through the GABAergic pathway.
The in vitro GABAergic activity of CTL was assessed via colorimetric assay, while acute toxicity was evaluated in Swiss mice per OECD guidelines with doses up to 2000 mg/kg to establish safety margins. Sedative effects were assessed in Swiss mice using thiopental sodium (TS, 40 mg/kg)-induced sleep protocols. CTL was administered at 62.5, 125, and 250 mg/kg doses, alone or combined with diazepam (DZP, 2 mg/kg) or flumazenil (FLU, 0.1 mg/kg). The in silico studies were also performed with GABA receptors (α1 and β2 subunits) to investigate the possible molecular mechanism.
The results demonstrated that in vitro, CTL exhibited significantly concentration-dependent GABAergic activity. Acute toxicity tests indicated a high safety margin (no behavioral or physiological abnormalities at 2000 mg/kg dose). Additionally, CTL significantly (p < 0.05) and dose-dependently reduced the latency and augmented sleep duration in animals, compared to the control group. It also significantly (p < 0.05) decreased the latency and increased the duration of sleep with DZP-2 while reducing this parameter with FLU-0.1. In in silico studies, CTL exhibited binding affinities (BAs) with the GABA receptor (α1 and β2 subunits) of -5.6 kcal/mol.
CTL demonstrated potent sedative effects in vitro and in vivo, with a strong safety profile and interaction with the GABA receptor (α1 and β2 subunits).
香茅醛（CTL）是一种单萜类化合物，主要通过γ-氨基丁酸（GABA）能途径表现出显著的神经活性，包括抗焦虑和抗惊厥作用。我们目前的研究旨在通过GABA能途径，采用体外、体内和计算机模拟方法探索CTL的镇静潜力。
通过比色法评估CTL的体外GABA能活性，同时按照经合组织（OECD）指南，在瑞士小鼠中以高达2000 mg/kg的剂量评估急性毒性，以确定安全范围。使用硫喷妥钠（TS，40 mg/kg）诱导睡眠方案，在瑞士小鼠中评估镇静效果。CTL以62.5、125和250 mg/kg的剂量单独给药，或与地西泮（DZP，2 mg/kg）或氟马西尼（FLU，0.1 mg/kg）联合给药。还对GABA受体（α1和β2亚基）进行了计算机模拟研究，以探究可能的分子机制。
结果表明，在体外，CTL表现出显著的浓度依赖性GABA能活性。急性毒性试验表明安全范围较高（2000 mg/kg剂量下无行为或生理异常）。此外，与对照组相比，CTL显著（p < 0.05）且剂量依赖性地缩短了动物的入睡潜伏期并延长了睡眠时间。它还显著（p < 0.05）缩短了与DZP-2合用的入睡潜伏期并增加了睡眠时间，而与FLU-0.1合用则降低了该参数。在计算机模拟研究中，CTL与GABA受体（α1和β2亚基）的结合亲和力（BA）为-5.6 kcal/mol。
CTL在体外和体内均表现出强效镇静作用，具有良好的安全性，并与GABA受体（α1和β2亚基）相互作用。
