Shikonin enhances hypnotic effect and synergistic properties of diazepam, possibly through GABAergic interaction pathway: In vivo and in silico studies

IF 1.7 4区医学 Q3 INTEGRATIVE & COMPLEMENTARY MEDICINE

European Journal of Integrative Medicine Pub Date : 2025-05-31 DOI:10.1016/j.eujim.2025.102508

Shipan Paul , Raihan Chowdhury , Md. Sakib Al Hasan , Md. Shimul Bhuia , Mohammed Alfaifi , Salehin Sheikh , Asraful Islam Rakib , Faysal Mollah , Shakil Ahmmed , Sharmita Ghosh Situ , Irfan Aamer Ansari , Siddique Akber Ansari , Debasree Sen Oisay , Muhammad Torequl Islam

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引用次数: 0

Abstract

Introduction

Shikonin is a natural naphthoquinone from Lithospermum erythrorhizon with diverse pharmacological activities, including neuroprotective, anti-inflammatory, and hypnotic effects.

Methods

The current study was focused on investigating the hypnotic effect and combination characteristics of shikonin with diazepam through in vivo and in silico studies. Swiss albino mice received shikonin (SKN-10 and SKN-20 mg/kg), diazepam (DZP-2 mg/kg) as a positive control, and a vehicle as a negative control (NC). Two combinations of SKN-10 and SKN-20 with DZP-2 were also administered before thiopental sodium-induced sleep to assess hypnosis and sedation. Different computational tools were utilized for molecular interaction and pharmacokinetics.

Results

In vivo study demonstrated that shikonin significantly (p < 0.05) increased sleep duration and reduced sleep latency in animals compared to the NC group. In addition to combination therapy, SKN-10 significantly enhanced the effect of diazepam compared to DZP-2 + SKN-20, resulting in the longest sleep duration and shortest latency, indicating the strongest hypnotic effects compared to the other groups. Moreover, molecular docking indicated that the shikonin showed strong binding affinity (BA) (−8.9 kcal/mol) compared to diazepam for the GABA_A receptor.

Conclusion

In summary, shikonin showed significant hypnotic and synergistic effects along with diazepam. Acute toxicity studies showed shikonin caused no behavioral changes, toxicity, or mortality in mice up to 20 mg/kg, suggesting a high safety margin, with the oral LD₅₀ likely exceeding 1g/kg. Future research should explore shikonin’s long-term effects, safety, and optimal dosage, particularly in clinical settings. In vitro studies on GABA_A interactions, combination therapy with diazepam, and cognitive, behavioral, and toxicity assessments are crucial for its safe use in CNS disorders.

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紫草素增强地西泮的催眠作用和协同特性，可能通过gaba能相互作用途径：体内和计算机研究

紫草素是紫草属植物中的天然萘醌类化合物，具有神经保护、抗炎、催眠等药理作用。方法通过体内和体外实验研究紫草素与地西泮的催眠作用及联用特点。瑞士白化小鼠以紫草素（SKN-10和SKN-20 mg/kg）、地西泮（DZP-2 mg/kg）为阳性对照，以载药为阴性对照（NC）。在硫喷妥钠诱导睡眠前给予SKN-10和SKN-20与DZP-2的两种组合，以评估催眠和镇静作用。不同的计算工具用于分子相互作用和药代动力学。结果体内实验表明，紫草素显著(p <；0.05)与NC组相比，小鼠睡眠持续时间增加，睡眠潜伏期减少。除联合治疗外，与DZP-2 + SKN-20相比，SKN-10显著增强了地西泮的作用，睡眠时间最长，潜伏期最短，催眠效果较其他组最强。此外，分子对接表明，与地西安定相比，紫草素对GABAA受体具有很强的结合亲和力（BA）（−8.9 kcal/mol）。结论紫草素与地西泮具有明显的协同催眠作用。急性毒性研究表明，紫草素在20mg /kg的剂量下不会引起小鼠行为改变、毒性或死亡，这表明紫草素具有很高的安全范围，口服LD50可能超过1g/kg。未来的研究应该探索紫草素的长期效果、安全性和最佳剂量，特别是在临床环境中。GABAA相互作用的体外研究、与地西泮联合治疗以及认知、行为和毒性评估对其在中枢神经系统疾病中的安全使用至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Integrative Medicine INTEGRATIVE & COMPLEMENTARY MEDICINE-

CiteScore

4.70

自引率

4.00%

发文量

102

审稿时长

33 days

期刊介绍： The European Journal of Integrative Medicine (EuJIM) considers manuscripts from a wide range of complementary and integrative health care disciplines, with a particular focus on whole systems approaches, public health, self management and traditional medical systems. The journal strives to connect conventional medicine and evidence based complementary medicine. We encourage submissions reporting research with relevance for integrative clinical practice and interprofessional education. EuJIM aims to be of interest to both conventional and integrative audiences, including healthcare practitioners, researchers, health care organisations, educationalists, and all those who seek objective and critical information on integrative medicine. To achieve this aim EuJIM provides an innovative international and interdisciplinary platform linking researchers and clinicians. The journal focuses primarily on original research articles including systematic reviews, randomized controlled trials, other clinical studies, qualitative, observational and epidemiological studies. In addition we welcome short reviews, opinion articles and contributions relating to health services and policy, health economics and psychology.