东莨菪亭通过调节炎症、氧化应激和单胺能途径减轻利血平诱导的小鼠疼痛-抑郁二元反应。

Scopoletin Attenuates Reserpine-Induced Pain-Depression Dyad in Mice via Modulation of Inflammation, Oxidative Stress, and Monoaminergic Pathways.

作者信息

Qnais Esam, Gammoh Omar, Bsieso Yousra, Aljabali Alaa A A, Alqudah Abdelrahim, Alawneh Zaid, Hajaj Hamzah, Alotaibi Badriyah S

机构信息

Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, 13133, Jordan.

Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, Irbid, 21163, Jordan.

出版信息

Neuromolecular Med. 2025 Jun 29;27(1):49. doi: 10.1007/s12017-025-08869-7.

DOI:10.1007/s12017-025-08869-7

PMID:40581693

Abstract

Pain and depression frequently are comorbid and have common mechanisms such as monoamine depletion, inflammation, and oxidative stress. Hence, this study aimed to investigate the effects of bioactive coumarin on reserpine induced pain-depression dyad in mice. Mechanical allodynia, depressive-like behavior, and cognitive deficits were induced by reserpine (0.5 mg/kg, subcutaneously, once daily on days 1-3) in male BALB/c mice. Scopoletin (50 mg/kg, p.o.) or gabapentin (10 mg/kg, p.o.) was given twice daily (at 9:00 am and 5:00 pm) for 5 days. For days 1-3, the initial daily dose of scopoletin or gabapentin was given 30 min before reserpine injection, with the second dose at the evening. Control animals, which received vehicle, were given 0.1% CMC. Behavioural tests (Electronic von Frey (eVF) test, Pressure Application Measurement (PAM) test) (Forced Swim Test (FST) and Morris Water Maze (MWM) test) were performed on day 4 and 6, and tissue collection was conducted on day 6 for biochemical analyses (cytokines (TNF-α and IL-1β), neurotransmitters (Serotonin, Norepinephrine, and Glutamate), MAO-A activity, GSH, TBARS). Paw withdrawal thresholds (eVF day 4: F(3,20) = 28.75, p < 0.001; PAM: F(3,20) = 35.17, p < 0.001) were markedly diminished and immobility time in FST (F(3,20) = 29.11, p < 0.001) was notably prolonged by reserpine. Moreover, it impaired the spatial memory (MWM: F(3,20) = 30.56, p < 0.001), and increased the serum TNF-α and IL-1β (F(3,20) = 24.32 and 18.50, respectively; p < 0.01), the brain MAO-A activity (F(3,20) = 16.83, p < 0.01), glutamate and TBARS (F(3,20) = 25.11, p < 0.001; F(3,20) = 19.76, p < 0.01), and decreased the brain serotonin, norepinephrine and GSH (p < 0.01-0.001). Supplementation with scopoletin markedly retarded deficits in behavior (eVF and PAL, p < 0.001; FST, p < 0.001; MWM, p < 0.001) and biochemistry (reduction of UG [TNF-α, IL-1β], MAO-A activity and glutamate level along with restoration of monoamine and antioxidant status, p < 0.05-0.001). Scopoletin is a promising candidate drug for comorbid pain and depression due to its significant counteracting effects on reserpine-induced behavioral and biochemical alterations.

摘要

疼痛和抑郁常常并存，且具有单胺耗竭、炎症和氧化应激等共同机制。因此，本研究旨在探讨生物活性香豆素对利血平诱导的小鼠疼痛 - 抑郁二元症的影响。通过给雄性BALB/c小鼠皮下注射利血平（0.5毫克/千克，每天一次，连续注射3天）来诱导机械性异常疼痛、抑郁样行为和认知缺陷。东莨菪素（50毫克/千克，口服）或加巴喷丁（10毫克/千克，口服）每天给药两次（上午9:00和下午5:00），持续5天。在第1 - 3天，东莨菪素或加巴喷丁的初始日剂量在注射利血平前30分钟给药，第二次剂量在晚上给药。接受赋形剂的对照动物给予0.1%的羧甲基纤维素（CMC）。在第4天和第6天进行行为测试（电子von Frey（eVF）测试、压力施加测量（PAM）测试、强迫游泳测试（FST）和莫里斯水迷宫（MWM）测试），并在第6天进行组织采集以进行生化分析（细胞因子（TNF-α和IL-1β）、神经递质（血清素、去甲肾上腺素和谷氨酸）、单胺氧化酶A（MAO-A）活性、谷胱甘肽（GSH）、丙二醛（TBARS））。利血平使爪部缩足阈值（eVF第4天：F(3,20) = 28.75，p < 0.001；PAM：F(3,20) = 35.17，p < 0.001）显著降低，FST中的不动时间（F(3,20) = 29.11，p < 0.001）显著延长。此外，它损害了空间记忆（MWM：F(3,20) = 30.56，p < 0.001），并增加了血清TNF-α和IL-1β（分别为F(3,20) = 24.32和18.50；p < 0.01）、脑MAO-A活性（F(3,20) = 16.83，p < 0.01）、谷氨酸和TBARS（F(3,20) = 25.11，p < 0.001；F(3,20) = 19.76，p < 0.01），并降低了脑血清素、去甲肾上腺素和GSH（p < 0.01 - 0.001）。补充东莨菪素显著减轻了行为（eVF和PAL，p < 0.001；FST，p < 0.001；MWM，p < 0.001）和生化方面的缺陷（降低UG [TNF-α，IL-1β]、MAO-A活性和谷氨酸水平，同时恢复单胺和抗氧化状态，p < 0.05 - 0.001）。由于东莨菪素对利血平诱导的行为和生化改变具有显著的对抗作用，它是一种治疗疼痛和抑郁共病的有前景的候选药物。