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：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

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.

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.	劉妍, 肖智權, 劉志英, 等. 普拉克索聯合艾地苯醌對帕金森患者炎性因子與氧化應激的影響. 醫學理論與實踐, 2023, 36(1): 45-47.
6.	徐朝輝, 陳瑛, 肖倩, 等. 艾地苯醌在帕金森病中的應用進展. 中國實用神經疾病雜志, 2021, 24(17): 1553-1564.
7.	崔麗霞, 郭麗云, 劉紅. 艾地苯醌聯合倍他司汀治療腦梗死后認知功能障礙的臨床研究. 現代藥物與臨床, 2023, 38(1): 85-90.
8.	楊珺, 楊露, 陶干, 等. 艾地苯醌聯合鹽酸多奈哌齊治療老年腦梗死后認知功能障礙的臨床療效及對腦神經代謝物和炎性因子的影響. 中國老年學雜志, 2023, 43(17): 4194-4197.
9.	侯錫鴻, 張佩林, 王斯嫻, 等. 芳香開竅中藥對中樞神經系統疾病的治療作用研究進展. 藥學進展, 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.	黃孔麗, 蘇世杰, 王玉婷, 等. 模式生物斑馬魚在神經退行性疾病中的研究進展. 中國比較醫學雜志, 2023, 33(10): 121-131.
14.	劉延英. 斑馬魚模型在神經退行性疾病研究中的應用進展. 中國實驗動物學報, 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, 高代麗, 王利振, 等. 小檗堿衍生物9-OH小檗堿的抗帕金森病活性和作用機制研究. 中國醫院藥學雜志, 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.	鄭海軍, 戴楠楠, 戴凱茜, 等. 艾地苯醌聯合依達拉奉對急性腦出血患者炎性因子和氧化應激水平的影響. 中國臨床藥學雜志, 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.	楊亞楠, 鄔芳艷, 王西新, 等. 基于斑馬魚模型評價二甲基姜黃素、黃芩苷、紫檀茋對異煙肼導致神經損傷的保護作用. 藥物評價研究, 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.	梁艷, 胡軍. 多巴胺轉運蛋白研究進展. 中國藥物濫用防治雜志, 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. 劉妍, 肖智權, 劉志英, 等. 普拉克索聯合艾地苯醌對帕金森患者炎性因子與氧化應激的影響. 醫學理論與實踐, 2023, 36(1): 45-47.
6. 徐朝輝, 陳瑛, 肖倩, 等. 艾地苯醌在帕金森病中的應用進展. 中國實用神經疾病雜志, 2021, 24(17): 1553-1564.
7. 崔麗霞, 郭麗云, 劉紅. 艾地苯醌聯合倍他司汀治療腦梗死后認知功能障礙的臨床研究. 現代藥物與臨床, 2023, 38(1): 85-90.
8. 楊珺, 楊露, 陶干, 等. 艾地苯醌聯合鹽酸多奈哌齊治療老年腦梗死后認知功能障礙的臨床療效及對腦神經代謝物和炎性因子的影響. 中國老年學雜志, 2023, 43(17): 4194-4197.
9. 侯錫鴻, 張佩林, 王斯嫻, 等. 芳香開竅中藥對中樞神經系統疾病的治療作用研究進展. 藥學進展, 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. 黃孔麗, 蘇世杰, 王玉婷, 等. 模式生物斑馬魚在神經退行性疾病中的研究進展. 中國比較醫學雜志, 2023, 33(10): 121-131.
14. 劉延英. 斑馬魚模型在神經退行性疾病研究中的應用進展. 中國實驗動物學報, 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, 高代麗, 王利振, 等. 小檗堿衍生物9-OH小檗堿的抗帕金森病活性和作用機制研究. 中國醫院藥學雜志, 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. 鄭海軍, 戴楠楠, 戴凱茜, 等. 艾地苯醌聯合依達拉奉對急性腦出血患者炎性因子和氧化應激水平的影響. 中國臨床藥學雜志, 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. 楊亞楠, 鄔芳艷, 王西新, 等. 基于斑馬魚模型評價二甲基姜黃素、黃芩苷、紫檀茋對異煙肼導致神經損傷的保護作用. 藥物評價研究, 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. 梁艷, 胡軍. 多巴胺轉運蛋白研究進展. 中國藥物濫用防治雜志, 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.

Journal of Biomedical Engineering

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

Abstract Full text Figures/Tables Video References Cited by

Format

Content