Neuroprotective effects of idebenone combined with borneol via the dopamine signaling pathway in a transgenic zebrafish model of Parkinson’s disease_Journal of Biomedical Engineering

Authors：

WANG Qifei ^1,2 , ZHONG Yayun ^1,2,3 , YANG Yanan ^1,2,3 , LIU Kechun ^1,2 ,  LIU Li ³ ,  ZHANG Yun ^1,2

1. Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250103, P. R. China;
2. Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan 250103, P. R. China;
3. School of Medical and Health Engineering, Changzhou University, Changzhou, Jiangsu 213164, P. R. China;

Corresponding author：

LIU Li, Email: xiaohan_0818@163.com; ZHANG Yun, Email: liulily@cczu.edu.cn

Keywords：

Transgenic zebrafish; Parkinson’s disease; Idebenone; Borneol; Dopamine signaling pathway

DOI：

10.7507/1001-5515.202401034

Video：

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The aim of this study is to investigate the protective effect of idebenone (IDE) combined with borneol (BO) against Parkinson’s disease (PD). In this study, wild-type AB zebrafish and transgenic Tg (vmat2: GFP) zebrafish with green fluorescence labeled dopamine neurons were used to establish the PD model with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP). Following drug treatment, the behavioral performance and dopamine neuron morphology of zebrafish were evaluated, and regulation of dopamine signaling pathway-related genes was determined using RT-qPCR. The results showed that IDE combined with BO improved the behavioral disorders of zebrafish such as bradykinesia and shortening movement distance, also effectively reversed the damage of MPTP-induced dopaminergic neurons. At the same time, the expression of dopamine synthesis and transportation-related genes was up-regulated, and the normal function of the signal transduction pathway was restored. The combination showed a better therapeutic effect compared to the IDE monotherapy group. This study reveals the protective mechanism of IDE combined with BO on the central nervous system for the first time, which provides an important experimental basis and theoretical reference for clinical combination strategy in PD treatment.

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4.	Bloem B R, Okun M S, Klein C. Parkinson’s disease. Lancet, 2021, 397(10291): 2284-2303.
5.	刘妍, 肖智权, 刘志英, 等. 普拉克索联合艾地苯醌对帕金森患者炎性因子与氧化应激的影响. 医学理论与实践, 2023, 36(1): 45-47.
6.	徐朝辉, 陈瑛, 肖倩, 等. 艾地苯醌在帕金森病中的应用进展. 中国实用神经疾病杂志, 2021, 24(17): 1553-1564.
7.	崔丽霞, 郭丽云, 刘红. 艾地苯醌联合倍他司汀治疗脑梗死后认知功能障碍的临床研究. 现代药物与临床, 2023, 38(1): 85-90.
8.	杨珺, 杨露, 陶干, 等. 艾地苯醌联合盐酸多奈哌齐治疗老年脑梗死后认知功能障碍的临床疗效及对脑神经代谢物和炎性因子的影响. 中国老年学杂志, 2023, 43(17): 4194-4197.
9.	侯锡鸿, 张佩林, 王斯娴, 等. 芳香开窍中药对中枢神经系统疾病的治疗作用研究进展. 药学进展, 2021, 45(5): 372-381.
10.	Kulkarni M, Sawant N, Kolapkar A, et al. Borneol: a promising monoterpenoid in enhancing drug delivery across various physiological barriers. AAPS PharmSciTech, 2021, 22(4): 145-161.
11.	Li Y, Ren M, Wang J, et al. Progress in borneol intervention for ischemic stroke: A systematic review. Front Pharmacol, 2021, 12: 606682-606704.
12.	Jiang P, Fu P, Xiang L, et al. The effectiveness of borneol on pharmacokinetics changes of four ginsenosides in Shexiang Baoxin Pill in vivo. Biomed Chromatogr, 2014, 28(3): 419-427.
13.	黄孔丽, 苏世杰, 王玉婷, 等. 模式生物斑马鱼在神经退行性疾病中的研究进展. 中国比较医学杂志, 2023, 33(10): 121-131.
14.	刘延英. 斑马鱼模型在神经退行性疾病研究中的应用进展. 中国实验动物学报, 2023, 31(10): 1361-1367.
15.	Pitchai A, Rajaretinam R K, Freeman J L. Zebrafish as an emerging model for bioassay-guided natural product drug discovery for neurological disorders. Medicines (Basel), 2019, 6(2): 61-80.
16.	牟蕾, 高代丽, 王利振, 等. 小檗碱衍生物9-OH小檗碱的抗帕金森病活性和作用机制研究. 中国医院药学杂志, 2022, 42(9): 884-888.
17.	Basnet R M, Zizioli D, Taweedet S, et al. Zebrafish larvae as a behavioral model in neuropharmacology. Biomedicines, 2019, 7(1): 23-38.
18.	郑海军, 戴楠楠, 戴凯茜, 等. 艾地苯醌联合依达拉奉对急性脑出血患者炎性因子和氧化应激水平的影响. 中国临床药学杂志, 2020, 29(5): 342-346.
19.	Zhou J, Yang Y, Zhao J, et al. Involvement of the weak metabolic function in cardiovascular toxicity induced by idebenone in zebrafish. Comp Biochem Phys C, 2025, 294: 110203-110211.
20.	Li B, Sun C, Yang Y, et al. Spatial metabolomics revealed multi-organ toxicity and visualize metabolite changes induced by borneol in zebrafish. Sci Total Environ, 2025, 968: 178886-178894.
21.	Dong L I, Zheng Y, Gao L, et al. LncRNA NEAT1 prompts autophagy and apoptosis in MPTP-induced Parkinson’s disease by impairing miR-374c-5p. Acta Biochim Biophys Sin, 2021, 53(7): 870-882.
22.	Chia S J, Tan E K, Chao Y X. Historical perspective: Models of Parkinson’s disease. Int J Mol Sci, 2020, 21(7): 2464-2477.
23.	杨亚楠, 邬芳艳, 王西新, 等. 基于斑马鱼模型评价二甲基姜黄素、黄芩苷、紫檀茋对异烟肼导致神经损伤的保护作用. 药物评价研究, 2021, 44(7): 1377-1384.
24.	Troshev D, Bannikova A, Blokhin V, et al. Striatal neurons partially expressing a dopaminergic phenotype: Functional significance and regulation. Int J Mol Sci, 2022, 23(19): 11054-11077.
25.	Rydzanicz M, Wachowska M, Cook E C, et al. Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression. Eur J Hum Genet, 2019, 27(1): 61-69.
26.	梁艳, 胡军. 多巴胺转运蛋白研究进展. 中国药物滥用防治杂志, 2003, 31(1): 56-60.
27.	Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother, 2014, 48(2): 209-225.
28.	Giordano N, Iemolo A, Mancini M, et al. Motor learning and metaplasticity in striatal neurons: relevance for Parkinson’s disease. Brain, 2018, 141(2): 505-520.
29.	Zhao T, Zondervan-van der Linde H, Severijnen L A, et al. Dopaminergic neuronal loss and dopamine-dependent locomotor defects in Fbxo7-deficient zebrafish. PLoS One, 2012, 7(11): e48911-48919.
30.	Maximino C, Herculano A M. A review of monoaminergic neuropsychopharmacology in zebrafish. Zebrafish, 2010, 7(4): 359-378.
31.	Boehmler W, Obrecht-Pflumio S, Canfield V, et al. Evolution and expression of D2 and D3 dopamine receptor genes in zebrafish. Dev Dyn, 2004, 230(3): 481-493.

1. Tolosa E, Garrido A, Scholz S W, et al. Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol, 2021, 20(5): 385-397.
2. Angelopoulou E, Paudel Y N, Shaikh M F, et al. Fractalkine (CX3CL1) signaling and neuroinflammation in Parkinson's disease: Potential clinical and therapeutic implications. Pharmacol Res, 2020, 158: 104930-104941.
3. Armstrong M J, Okun M S. Diagnosis and treatment of Parkinson disease: A review. JAMA, 2020, 323(6): 548-560.
4. Bloem B R, Okun M S, Klein C. Parkinson’s disease. Lancet, 2021, 397(10291): 2284-2303.
5. 刘妍, 肖智权, 刘志英, 等. 普拉克索联合艾地苯醌对帕金森患者炎性因子与氧化应激的影响. 医学理论与实践, 2023, 36(1): 45-47.
6. 徐朝辉, 陈瑛, 肖倩, 等. 艾地苯醌在帕金森病中的应用进展. 中国实用神经疾病杂志, 2021, 24(17): 1553-1564.
7. 崔丽霞, 郭丽云, 刘红. 艾地苯醌联合倍他司汀治疗脑梗死后认知功能障碍的临床研究. 现代药物与临床, 2023, 38(1): 85-90.
8. 杨珺, 杨露, 陶干, 等. 艾地苯醌联合盐酸多奈哌齐治疗老年脑梗死后认知功能障碍的临床疗效及对脑神经代谢物和炎性因子的影响. 中国老年学杂志, 2023, 43(17): 4194-4197.
9. 侯锡鸿, 张佩林, 王斯娴, 等. 芳香开窍中药对中枢神经系统疾病的治疗作用研究进展. 药学进展, 2021, 45(5): 372-381.
10. Kulkarni M, Sawant N, Kolapkar A, et al. Borneol: a promising monoterpenoid in enhancing drug delivery across various physiological barriers. AAPS PharmSciTech, 2021, 22(4): 145-161.
11. Li Y, Ren M, Wang J, et al. Progress in borneol intervention for ischemic stroke: A systematic review. Front Pharmacol, 2021, 12: 606682-606704.
12. Jiang P, Fu P, Xiang L, et al. The effectiveness of borneol on pharmacokinetics changes of four ginsenosides in Shexiang Baoxin Pill in vivo. Biomed Chromatogr, 2014, 28(3): 419-427.
13. 黄孔丽, 苏世杰, 王玉婷, 等. 模式生物斑马鱼在神经退行性疾病中的研究进展. 中国比较医学杂志, 2023, 33(10): 121-131.
14. 刘延英. 斑马鱼模型在神经退行性疾病研究中的应用进展. 中国实验动物学报, 2023, 31(10): 1361-1367.
15. Pitchai A, Rajaretinam R K, Freeman J L. Zebrafish as an emerging model for bioassay-guided natural product drug discovery for neurological disorders. Medicines (Basel), 2019, 6(2): 61-80.
16. 牟蕾, 高代丽, 王利振, 等. 小檗碱衍生物9-OH小檗碱的抗帕金森病活性和作用机制研究. 中国医院药学杂志, 2022, 42(9): 884-888.
17. Basnet R M, Zizioli D, Taweedet S, et al. Zebrafish larvae as a behavioral model in neuropharmacology. Biomedicines, 2019, 7(1): 23-38.
18. 郑海军, 戴楠楠, 戴凯茜, 等. 艾地苯醌联合依达拉奉对急性脑出血患者炎性因子和氧化应激水平的影响. 中国临床药学杂志, 2020, 29(5): 342-346.
19. Zhou J, Yang Y, Zhao J, et al. Involvement of the weak metabolic function in cardiovascular toxicity induced by idebenone in zebrafish. Comp Biochem Phys C, 2025, 294: 110203-110211.
20. Li B, Sun C, Yang Y, et al. Spatial metabolomics revealed multi-organ toxicity and visualize metabolite changes induced by borneol in zebrafish. Sci Total Environ, 2025, 968: 178886-178894.
21. Dong L I, Zheng Y, Gao L, et al. LncRNA NEAT1 prompts autophagy and apoptosis in MPTP-induced Parkinson’s disease by impairing miR-374c-5p. Acta Biochim Biophys Sin, 2021, 53(7): 870-882.
22. Chia S J, Tan E K, Chao Y X. Historical perspective: Models of Parkinson’s disease. Int J Mol Sci, 2020, 21(7): 2464-2477.
23. 杨亚楠, 邬芳艳, 王西新, 等. 基于斑马鱼模型评价二甲基姜黄素、黄芩苷、紫檀茋对异烟肼导致神经损伤的保护作用. 药物评价研究, 2021, 44(7): 1377-1384.
24. Troshev D, Bannikova A, Blokhin V, et al. Striatal neurons partially expressing a dopaminergic phenotype: Functional significance and regulation. Int J Mol Sci, 2022, 23(19): 11054-11077.
25. Rydzanicz M, Wachowska M, Cook E C, et al. Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression. Eur J Hum Genet, 2019, 27(1): 61-69.
26. 梁艳, 胡军. 多巴胺转运蛋白研究进展. 中国药物滥用防治杂志, 2003, 31(1): 56-60.
27. Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother, 2014, 48(2): 209-225.
28. Giordano N, Iemolo A, Mancini M, et al. Motor learning and metaplasticity in striatal neurons: relevance for Parkinson’s disease. Brain, 2018, 141(2): 505-520.
29. Zhao T, Zondervan-van der Linde H, Severijnen L A, et al. Dopaminergic neuronal loss and dopamine-dependent locomotor defects in Fbxo7-deficient zebrafish. PLoS One, 2012, 7(11): e48911-48919.
30. Maximino C, Herculano A M. A review of monoaminergic neuropsychopharmacology in zebrafish. Zebrafish, 2010, 7(4): 359-378.
31. Boehmler W, Obrecht-Pflumio S, Canfield V, et al. Evolution and expression of D2 and D3 dopamine receptor genes in zebrafish. Dev Dyn, 2004, 230(3): 481-493.

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Latest ArticlesNeuroprotective effects of idebenone combined with borneol via the dopamine signaling pathway in a transgenic zebrafish model of Parkinson’s disease

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