Neuroprotective potential of proanthocyanidins and anthocyanidins against rotenone-induced neurotoxicity: a review across animal and drosophila models
DOI:
https://doi.org/10.4314/wnjms.v8i1.11Keywords:
Rotenone toxicity, Neurodegenerative diseases, Proanthocyanidins, Anthocyanidins, Oxidative stressAbstract
Introduction: Rotenone, a natural pesticide and neurotoxin, is commonly used to replicate key features of Parkinson’s disease in experimental models due to its ability to disrupt mitochondrial function and trigger oxidative stress, inflammation, and neuronal damage. As interest grows in plant-based therapies, compounds like proanthocyanidins and anthocyanidins found in berries, grape seeds, and colourful fruits, have shown beneficial effects due to their antioxidant and neuroprotective effects. These phytochemicals may counteract the harmful effects of rotenone by preserving mitochondrial health and reducing inflammation. This review aims to synthesize existing evidence on the protective roles of proanthocyanidins and anthocyanidins in animal and Drosophila models exposed to rotenone.
Methods: This review draws on a broad literature search across PubMed, Scopus, and Web of Science to summarize current evidence on how proanthocyanidins and anthocyanidins protect against rotenone-induced toxicity.
Results: Key findings indicate that these compounds effectively reduce oxidative stress markers, improve mitochondrial integrity, and alleviate motor deficits in both models. Comparative analysis reveals similarities in mechanisms of action across species while highlighting differences in experimental approaches and outcomes.
Conclusion: Despite the promising preclinical results, significant gaps remain in translating these findings into human clinical applications. Standardized dosing regimens, deeper mechanistic studies, and clinical trials are essential to harness their full therapeutic potential. This review emphasizes the need for continued exploration of proanthocyanidins and anthocyanidins as adjunctive therapies in neurodegenerative diseases, particularly Parkinson’s disease, offering a pathway toward novel, plant-derived interventions for human health.
References
Zhang P, Qin D, Chen J, Zhang Z. Plants in the genus Tephrosia: valuable resources for botanical insecticides. Insects. 2020; 11(10):721. https://doi.org/10.3390/insects11100721
Okwute SK, Egharevba HO. Insecticidal Agents in Pest Control: Sources, Challenges, and Advantages. 2024. https://doi.org/10.5772/intechopen.1005886
Choi E-H, Kim M-H, Park S-J. Targeting mitochondrial dysfunction and reactive oxygen species for neurodegenerative disease treatment. Int J Mol Sci. 2024; 25(14):7952. https://doi.org/10.3390/ijms25147952
Khan E, Hasan I, Haque ME. Parkinson’s disease: exploring different animal model systems. Int J Mol Sci. 2023; 24(10):9088. https://doi.org/10.3390/ijms24109088
Ullah R, Khan M, Shah SA, Saeed K, Kim MO. Natural antioxidant anthocyanins—A hidden therapeutic candidate in metabolic disorders with major focus in neurodegeneration. Nutrients. 2019; 11(6):1195. https://doi.org/10.3390/nu11061195
Rauf A, Imran M, Abu-Izneid T, Patel S, Pan X, Naz S, et al. Proanthocyanidins: A comprehensive review. Biomed Pharmacother. 2019; 116:108999. https://doi.org/10.1016/j.biopha.2019.108999
Pham D-C, Shibu M, Mahalakshmi B, Velmurugan BK. Effects of phytochemicals on cellular signaling: reviewing their recent usage approaches. Crit Rev Food Sci Nutr. 2020; 60(20):3522-46. https://doi.org/10.1080/10408398.2019.1699014
Mattioli R, Francioso A, Mosca L, Silva P. Anthocyanins: A comprehensive review of their chemical properties and health effects on cardiovascular and neurodegenerative diseases. Molecules. 2020; 25(17):3809. https://doi.org/10.3390/molecules25173809
Sapian S, Taib IS, Latip J, Katas H, Chin K-Y, Mohd Nor NA, et al. Therapeutic approach of flavonoid in ameliorating diabetic cardiomyopathy by targeting mitochondrial-induced oxidative stress. Int J Mol Sci. 2021; 22(21):11616. https://doi.org/10.3390/ijms222111616
Winter AN, Bickford PC. Anthocyanins and their metabolites as therapeutic agents for neurodegenerative disease. Antioxidants. 2019; 8(9):333. https://doi.org/10.3390/antiox8090333
Heinz S, Freyberger A, Lawrenz B, Schladt L, Schmuck G, Ellinger-Ziegelbauer H. Mechanistic investigations of the mitochondrial complex I inhibitor rotenone in the context of pharmacological and safety evaluation. Sci Rep. 2017; 7(1):1–13. https://doi.org/10.1038/srep45465
Sachdev S, Ansari SA, Ansari MI, Fujita M, Hasanuzzaman M. Abiotic stress and reactive oxygen species: Generation, signaling, and defense mechanisms. Antioxidants. 2021; 10(2):277. https://doi.org/10.3390/antiox10020277
Tian M, Cao H, Gao H, Zhu L, Wu Y, Li G. Rotenone-induced cell apoptosis via endoplasmic reticulum stress and PERK-eIF2α-CHOP signalling pathways in TM3 cells. Ecotoxicol Environ Saf. 2024; 284:116972. https://doi.org/10.1016/j.ecoenv.2024.116972
Eddin LB, Azimullah S, Jha NK, Nagoor Meeran MF, Beiram R, Ojha S. Limonene, a monoterpene, mitigates rotenone-induced dopaminergic neurodegeneration by modulating neuroinflammation, hippo signaling and apoptosis in rats. Int J Mol Sci. 2023; 24(6):5222. https://doi.org/10.3390/ijms24065222
Rocha SM, Bantle CM, Aboellail T, Chatterjee D, Smeyne RJ, Tjalkens RB. Rotenone induces regionally distinct α-synuclein protein aggregation and activation of glia prior to loss of dopaminergic neurons in C57Bl/6 mice. Neurobiol Dis. 2022; 167:105685. https://doi.org/10.1016/j.nbd.2022.105685
Victor AA, Aja PM, Shinkafi TS, Ondari EN, Adeniyi AI, Fasogbon IV, et al. Exploring the versatility of Drosophila melanogaster as a model organism in biomedical research: a comprehensive review. Fly (Austin). 2025; 19(1):2420453. https://doi.org/10.1080/19336934.2024.2420453
Jeibmann A, Paulus W. Drosophila melanogaster as a model organism of brain diseases. International journal of molecular sciences. 2009; 10(2):407-40.).
Qi Q, Chu M, Yu X, Xie Y, Li Y, Du Y, et al. Anthocyanins and proanthocyanidins: Chemical structures, food sources, bioactivities, and product development. Food Rev Int. 2023; 39(7):4581–609. https://doi.org/10.1080/87559129.2022.2029479
Vo TTT, Chu P-M, Tuan VP, Te JS-L, Lee I-T. The promising role of antioxidant phytochemicals in the prevention and treatment of periodontal disease via the inhibition of oxidative stress pathways: Updated insights. Antioxidants. 2020; 9(12):1211. https://doi.org/10.3390/antiox9121211
Shin SA, Joo BJ, Lee JS, Ryu G, Han M, Kim WY, et al. Phytochemicals as anti-inflammatory agents in animal models of prevalent inflammatory diseases. Molecules. 2020; 25(24):5932. https://doi.org/10.3390/molecules25245932
Rekatsina M, Paladini A, Piroli A, Zis P, Pergolizzi JV, Varrassi G. Pathophysiology and therapeutic perspectives of oxidative stress and neurodegenerative diseases: a narrative review. Adv Ther. 2020; 37:113–39. https://doi.org/10.1007/s12325-019-01148-5
Ibarra-Gutiérrez MT, Serrano-García N, Orozco-Ibarra M. Rotenone-induced model of Parkinson’s disease: Beyond mitochondrial complex I inhibition. Mol Neurobiol. 2023; 60(4):1929–48. https://doi.org/10.1007/s12035-022-03193-8
Sun Q, Jia N, Li X, Yang J, Chen G. Grape seed proanthocyanidins ameliorate neuronal oxidative damage by inhibiting GSK-3β-dependent mitochondrial permeability transition pore opening in an experimental model of sporadic Alzheimer’s disease. Aging (Albany NY). 2019; 11(12):4107. https://doi.org/10.18632/aging.102041
Chen H-W, Liu M-Q, Zhang G-Z, Zhang C-Y, Wang Z-H, Lin A-X, et al. Proanthocyanidins inhibit the apoptosis and aging of nucleus pulposus cells through the PI3K/Akt pathway delaying intervertebral disc degeneration. Connect Tissue Res. 2022; 63(6):650–62. https://doi.org/10.1080/03008207.2022.2063121
Moratilla-Rivera I, Sánchez M, Valdés-González JA, Gómez-Serranillos MP. Natural products as modulators of Nrf2 signaling pathway in neuroprotection. Int J Mol Sci. 2023; 24(4):3748. https://doi.org/10.3390/ijms24043748
Tabeshpour J, Mehri S, Shaebani Behbahani F, Hosseinzadeh H. Protective effects of Vitis vinifera (grapes) and one of its biologically active constituents, resveratrol, against natural and chemical toxicities: A comprehensive review. Phytother Res. 2018; 32(11):2164–90. https://doi.org/10.1002/ptr.6168
Pogačnik L, Ota A, Poklar Ulrih N. An overview of crucial dietary substances and their modes of action for prevention of neurodegenerative diseases. Cells. 2020; 9(3):576. https://doi.org/10.3390/cells9030576
Marques-da-Silva D, Rodrigues JR, Lagoa R. Anthocyanins, effects in mitochondria and metabolism. In: Mitochondrial Physiology and Vegetal Molecules. Elsevier; 2021. p. 267–300. https://doi.org/10.1016/b978-0-12-821562-3.00028-9
de Oliveira NK, Almeida MRS, Pontes FMM, Barcelos MP, de Paula da Silva CHT, Rosa JMC, et al. Antioxidant effect of flavonoids present in Euterpe oleracea Martius and neurodegenerative diseases: A literature review. Cent Nerv Syst Agents Med Chem. 2019; 19(2):75–99. https://doi.org/10.2174/1871524919666190502105855
Li P, Feng D, Yang D, Li X, Sun J, Wang G, Tian L, Jiang X, Bai W. Protective effects of anthocyanins on neurodegenerative diseases. Trends in Food Science & Technology. 2021; 117:205-17.
Bernardo MC, Santos CE, Mabalot ME, Nas JS. Petunidin-3-glucoside supplementation causes sex-specific effects on the lifespan and motor function in(textit {Drosophila melanogaster}). Academia Journal of Biology. 2024; 46(1):1-2.
Fikry H, Saleh LA, Abdel Gawad S. Neuroprotective effects of curcumin on the cerebellum in a rotenone‐induced Parkinson’s disease model. CNS Neurosci Ther. 2022; 28(5):732–48. https://doi.org/10.1111/cns.13805
Asthana J, Shravage BV. Exploring therapeutic potential of mitophagy modulators using Drosophila models of Parkinson’s disease. Front Aging Neurosci. 2022; 14:986849. https://doi.org/10.3389/fnagi.2022.986849
Ayajuddin M, Phom L, Koza Z, Modi P, Das A, Chaurasia R, et al. Adult health and transition stage-specific rotenone-mediated Drosophila model of Parkinson’s disease: Impact on late-onset neurodegenerative disease models. Frontiers in molecular neuroscience. 2022; 15:896183.
Asthana J, Shravage BV. Exploring therapeutic potential of mitophagy modulators using Drosophila models of Parkinson’s disease. Frontiers in Aging Neuroscience. 2022; 14:986849.
Johri A, Chandra A. Mitochondria in Huntington’s Disease. In: Antioxidants and Functional Foods for Neurodegenerative Disorders. CRC Press; 2021. p. 129–50. https://doi.org/10.1201/9780429319310-11
Rius-Pérez S, Torres-Cuevas I, Millán I, Ortega ÁL, Pérez S. PGC‐1α, inflammation, and oxidative stress: an integrative view in metabolism. Oxid Med Cell Longev. 2020; 2020(1):1452696. https://doi.org/10.1155/2020/1452696
Gureev AP, Shaforostova EA, Popov VN. Regulation of mitochondrial biogenesis as a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Front Genet. 2019; 10:435. https://doi.org/10.3389/fgene.2019.00435
Ponnampalam EN, Kiani A, Santhiravel S, Holman BW, Lauridsen C, Dunshea FR. The importance of dietary antioxidants on oxidative stress, meat and milk production, and their preservative aspects in farm animals: Antioxidant action, animal health, and product quality—Invited review. Animals (Basel). 2022; 12(23):3279. https://doi.org/10.3390/ani12233279
Lin BW, Gong CC, Song HF, Cui YY. Effects of anthocyanins on the prevention and treatment of cancer. British journal of pharmacology. 2017; 174(11):1226-43)
Sobeh M, Mahmoud MF, Abdelfattah MA, Cheng H, El-Shazly AM, Wink M. A proanthocyanidin-rich extract from Cassia abbreviata exhibits antioxidant and hepatoprotective activities in vivo. J Ethnopharmacol. 2018; 213:38–47. https://doi.org/10.1016/j.jep.2017.11.007
Zhu F. Anthocyanins in cereals: Composition and health effects. Food Res Int. 2018; 109:232–49. https://doi.org/10.1016/j.foodres.2018.04.015
Palasz E, Niewiadomski W, Gasiorowska A, Wysocka A, Stepniewska A, Niewiadomska G. Exercise-induced neuroprotection and recovery of motor function in animal models of Parkinson's disease. Front Neurol. 2019; 10:1143. https://doi.org/10.3389/fneur.2019.01143
Stavinoha RC. In vivo neuroprotective effects of cinnamon bioactive compounds in C. elegans and D. melanogaster. 2015. https://digital.library.txst.edu/server/api/core/bitstreams/db5e9d2e-3ec5-47d3-ba23-8ed248c0ac67/content (Date Accessed:......)
Dreiseitel A. In vitro bioactivities of dietary anthocyanins and proanthocyanidins: implications for bioavailability, neuroprotection and safety (Doctoral dissertation, Universität Würzburg). Available at:…….. (Date Accessed:……)
Yang K, Lv Z, Zhao W, Lai G, Zheng C, Qi F, et al. The potential of natural products to inhibit abnormal aggregation of α-Synuclein in the treatment of Parkinson’s disease. Front Pharmacol. 2024; 15:1468850. https://doi.org/10.3389/fphar.2024.1468850
Zhong H, Xu J, Yang M, Hussain M, Liu X, Feng F, et al. Protective effect of anthocyanins against neurodegenerative diseases through the microbial-intestinal-brain axis: a critical review. Nutrients. 2023; 15(3):496. https://doi.org/10.3390/nu15030496
Pihlstrøm L, Wiethoff S, Houlden H. Genetics of neurodegenerative diseases: an overview. Handb Clin Neurol. 2018; 145:309–23. https://doi.org/10.1016/b978-0-12-802395-2.00022-5
Salehi B, Sharifi-Rad J, Cappellini F, Reiner Ž, Zorzan D, Imran M, et al. The therapeutic potential of anthocyanins: current approaches based on their molecular mechanism of action. Front Pharmacol. 2020; 11:1300. https://doi.org/10.3389/fphar.2020.01300
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