Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The standard treatments for PD focus on symptom relief rather than attempting to address the underlying degenerative processes completely. This study aimed to evaluate the potential therapeutic effects of policosanol derived from insect wax (PIW) by investigating improvements in disease symptoms represented in Caenorhabditis elegans models of PD. For our assessments, we used the following three models: NL5901, which is a transgenic model for α-synuclein aggregation; wild-type N2 induced with 6-hydroxydopamine (6-OHDA); and 6-OHDA-induced BZ555 as a model for loss of dopaminergic neurons (DNs). Specifically, we examined the effects of PIW treatment on α-synuclein aggregation, the loss of DNs, lipid abundance, and the lifespan of treated organisms. Further, we examined treatment-related changes in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), adenosine triphosphate (ATP), glutathione S-transferase (GST), and superoxide dismutase (SOD), as well as the mRNA production profiles of relevant genes. A 10 µg/mL dose of PIW reduced the aggregation of α-synuclein in NL5901 and suppressed the loss of DNs in 6-OHDA-induced BZ555. Overall, PIW treatment decreased ROS and MDA levels, restored lipid abundance, and prolonged the lifespans of worms in all the three models, which may be associated with changes in the expression profiles of genes related to cell survival and oxidative stress response pathways. Our findings show that PIW alleviated the symptoms of PD in these models, possibly by regulating the stress responses initiated by injuries such as α-synuclein aggregation or 6-OHDA treatment.
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Abbreviations
- 6-OHDA:
-
6-Hydroxydopamine
- ADEs:
-
Anterior deirid neurons
- ATP:
-
Adenosine triphosphate
- CEPs:
-
Anterior cephalic neurons
- DNs:
-
Dopaminergic neurons
- FUDR:
-
5-Fluoro-2'-deoxyuridine
- GFP:
-
Green fluorescent protein
- GST:
-
Glutathione S-transferase
- MDA:
-
Malondialdehyde
- NGM:
-
Nematode growth media
- PD:
-
Parkinson's disease
- PIW:
-
Policosanol extracted from the insect wax
- ROS:
-
Reactive oxygen species
- SEM:
-
Standard error of the mean
- SOD:
-
Superoxide dismutase
- YFP:
-
Yellow fluorescent protein
References
Angelova PR, Horrocks MH, Klenerman D, Gandhi S, Abramov AY, Shchepinov MS (2015) Lipid peroxidation is essential for alpha-synuclein-induced cell death. J Neurochem 133:582–589. https://doi.org/10.1111/jnc.13024
Askarpour M, Ghaedi E, Roshanravan N, Hadi A, Mohammadi H, Symonds ME, Miraghajani M (2019) Policosanol supplementation significantly improves blood pressure among adults: A systematic review and meta-analysis of randomized controlled trials. Complement Ther Med 45:89–97. https://doi.org/10.1016/j.ctim.2019.05.023
Bartels T (2019) Alpha-Synuclein Methods and Protocols. Humana Press, New York. https://doi.org/10.1007/978-1-4939-9124-2
Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, Verna JM (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, Molecular pathways involved in the neurotoxicity of 6-OHDA. Prog Neurobiol 65:135–172. https://doi.org/10.1016/s0301-0082(01)00003-x
Castano G, Arruzazabala ML, Fernandez L, Mas R, Carbajal D, Molina V, Illnait J, Mendoza S, Gamez R, Mesa M, Fernandes S (2006) Effects of Combination Treatment with Policosanol and Omega-3 Fatty Acids on Platelet Aggregation A Randomized, Double-Blind Clinical Study. Curr Ther Res Clin Exp 67:174–192. https://doi.org/10.1016/j.curtheres.2006.06.004
Chalorak P, Jattujan P, Nobsathian S, Poomtong T, Sobhon P, Meemon K (2018) Holothuria scabra extracts exhibit anti-Parkinson potential in C. elegans: A model for anti-Parkinson testing. Nutr Neurosci 21:427–438. https://doi.org/10.1080/1028415X.2017.1299437
Chalorak P, Dharmasaroja P, Meemon K (2020) Downregulation of eEF1A/EFT3–4 Enhances Dopaminergic Neurodegeneration After 6-OHDA Exposure in C. elegans Model. Front Neurosci 14:303. https://doi.org/10.3389/fnins.2020.00303
Chang CH, Wei CC, Ho CT, Liao VH (2021) N-gamma-(L-glutamyl)-L-selenomethionine shows neuroprotective effects against Parkinson’s disease associated with SKN-1/Nrf2 and TRXR-1 in Caenorhabditis elegans. Phytomedicine 92:153733. https://doi.org/10.1016/j.phymed.2021.153733
Chen XM (2011) Natural population ecology of Ericerus pela. Science Press, Beijing
Chen XM, Feng Y (2009) An introduction to resource entomology. Science Press, Beijing
Chen F, Hersh BM, Conradt B, Zhou Z, Riemer D, Gruenbaum Y, Horvitz HR (2000) Translocation of C. elegans CED-4 to Nuclear Membranes During Programmed Cell Death. Science 287:1485–1489. https://doi.org/10.1126/science.287.5457.1485
Cho KH, Kim SJ, Yadav D, Kim JY, Kim JR (2018) Consumption of Cuban Policosanol Improves Blood Pressure and Lipid Profile via Enhancement of HDL Functionality in Healthy Women Subjects: Randomized, Double-Blinded, and Placebo-Controlled Study. Oxid Med Cell Longev 2018:4809525. https://doi.org/10.1155/2018/4809525
Ciulla M, Marinelli L, Cacciatore I, Stefano AD (2019) Role of Dietary Supplements in the Management of Parkinson's Disease. Biomolecules 9. https://doi.org/10.3390/biom9070271
Cooper JF, Van Raamsdonk JM (2018) Modeling Parkinson’s Disease in C. elegans. J Parkinsons Dis 8:17–32. https://doi.org/10.3233/JPD-171258
de Lau LML, Breteler MMB (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535. https://doi.org/10.1016/s1474-4422(06)70471-9
Devos D, Hirsch E, Wyse R (2021) Seven Solutions for Neuroprotection in Parkinson’s Disease. Mov Disord 36:306–316. https://doi.org/10.1002/mds.28379
Duangjan C, Rangsinth P, Gu X, Zhang S, Wink M, Tencomnao T (2019) Glochidion zeylanicum leaf extracts exhibit lifespan extending and oxidative stress resistance properties in Caenorhabditis elegans via DAF-16/FoxO and SKN-1/Nrf-2 signaling pathways. Phytomedicine 64. https://doi.org/10.1016/j.phymed.2019.153061
Escorcia W, Ruter DL, Nhan J, Curran SP (2018) Quantification of Lipid Abundance and Evaluation of Lipid Distribution in Caenorhabditis elegans by Nile Red and Oil Red O Staining. J Vis Exp. https://doi.org/10.3791/57352
Farrer MJ (2006) Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 7:306–318. https://doi.org/10.1038/nrg1831
Flower TR, Chesnokova LS, Froelich CA, Dixon C, Witt SN (2005) Heat shock prevents alpha-synuclein-induced apoptosis in a yeast model of Parkinson’s disease. J Mol Biol 351:1081–1100. https://doi.org/10.1016/j.jmb.2005.06.060
Galvagnion C (2017) The Role of Lipids Interacting with alpha-Synuclein in the Pathogenesis of Parkinson’s Disease. J Parkinsons Dis 7:433–450. https://doi.org/10.3233/JPD-171103
Gong J, Qin X, Yuan F, Hu M, Chen G, Fang K, Wang D, Jiang S, Li J, Zhao Y, Huang Z, Dong H, Lu F (2018) Efficacy and safety of sugarcane policosanol on dyslipidemia: A meta-analysis of randomized controlled trials. Mol Nutr Food Res 62. https://doi.org/10.1002/mnfr.201700280
González R, Paz M, Amiela T, Morera F, Illnait J (2018) Effect of policosanol (20 mg/d) on the functional recovery of patients with ischemic stroke: a one year study. Revista CENIC Ciencias Biologicas 49:1–14
Gouni-Berthold I, Berthold HK (2002) Policosanol: clinical pharmacology and therapeutic significance of a new lipid-lowering agent. Am Heart J 143:356–365. https://doi.org/10.1067/mhj.2002.119997
Granja AL, Hernandez JM, Quintana DC, Valmana LA, Ferreiro RM, Mesa MG (1999) A mixture of higher primary aliphatic alcohols, its obtention from sugar cane wax and its pharmaceutical uses. Patent Publication No: AU711756B2
Hartman JH, Gonzalez-Hunt C, Hall SM, Ryde IT, Caldwell KA, Caldwell GA, Meyer JN (2019) Genetic Defects in Mitochondrial Dynamics in Caenorhabditis elegans Impact Ultraviolet C Radiation- and 6-hydroxydopamine-Induced Neurodegeneration. Int J Mol Sci 20. https://doi.org/10.3390/ijms20133202
Hayes MT (2019) Parkinson’s Disease and Parkinsonism. Am J Med 132:802–807. https://doi.org/10.1016/j.amjmed.2019.03.001
Kabir Y (2020) Health Benefits of Octacosanol and Other Long-Chain Aliphatic Fatty Alcohols from Plants. Springer Nature, Singapore
Kampkotter A, Pielarski T, Rohrig R, Timpel C, Chovolou Y, Watjen W, Kahl R (2007) The Ginkgo biloba extract EGb761 reduces stress sensitivity, ROS accumulation and expression of catalase and glutathione S-transferase 4 in Caenorhabditis elegans. Pharmacol Res 55:139–147. https://doi.org/10.1016/j.phrs.2006.11.006
Kim JY, Kim SM, Kim SJ, Lee EY, Kim JR, Cho KH (2017) Consumption of policosanol enhances HDL functionality via CETP inhibition and reduces blood pressure and visceral fat in young and middle-aged subjects. Int J Mol Med 39:889–899. https://doi.org/10.3892/ijmm.2017.2907
Kim SK, van Ham TJ, Thijssen KL, Breitling R, Hofstra RMW, Plasterk RHA, Nollen EAA (2008) C. elegans Model Identifies Genetic Modifiers of α-Synuclein Inclusion Formation During Aging. PLoS Genetics 4. https://doi.org/10.1371/journal.pgen.1000027
Kim SJ, Yadav D, Park HJ, Kim JR, Cho KH (2018) Long-Term Consumption of Cuban Policosanol Lowers Central and Brachial Blood Pressure and Improves Lipid Profile With Enhancement of Lipoprotein Properties in Healthy Korean Participants. Front Physiol 9. https://doi.org/10.3389/fphys.2018.00412
Lang AE, Espay AJ (2018) Disease Modification in Parkinson’s Disease: Current Approaches, Challenges, and Future Considerations. Mov Disord 33:660–677. https://doi.org/10.1002/mds.27360
Li H, Shi R, Ding F, Wang H, Han W, Ma F, Hu M, Ma CW, Huang Z (2016) Astragalus Polysaccharide Suppresses 6-Hydroxydopamine-Induced Neurotoxicity in Caenorhabditis elegans. Oxid Med Cell Longev 2016:4856761. https://doi.org/10.1155/2016/4856761
Ligaard J, Sannaes J, Pihlstrom L (2019) Deep brain stimulation and genetic variability in Parkinson’s disease: a review of the literature. NPJ Parkinsons Dis 5:18. https://doi.org/10.1038/s41531-019-0091-7
Lu L, Shu C, Chen L, Yang Y, Ma S, Zhu K, Shi B (2020) Insecticidal activity and mechanism of cinnamaldehyde in C. elegans. Fitoterapia 146:104687. https://doi.org/10.1016/j.fitote.2020.104687
Ludtmann MHR, Abramov AY (2018) Mitochondrial calcium imbalance in Parkinson’s disease. Neurosci Lett 663:86–90. https://doi.org/10.1016/j.neulet.2017.08.044
Ma JJ, Ma LY, Zhang H, Zhang ZQ, Wang YQ (2018a) The preparation and evaluation of efficacy on skin wound healing in mice of insect wax compound ointment. Journal of Environmental Entomology 40:1238–1247. https://doi.org/10.3969/j.issn.1674-0858.2018.06.6
Ma J, Wang R, Chen T, Jiang S, Xu A (2021) Protective effects of baicalin in a Caenorhabditis elegans model of Parkinson’s disease. Toxicol Res (camb) 10:409–417. https://doi.org/10.1093/toxres/tfaa107
Ma JJ, Li K, Zhang WW, Ma LY, Xu J, Liu LX, Chen XM, Zhang H (2022) Acute toxicity and chromosomal aberration toxicity of insect wax and its policosanol. Food Sci Human Wellness 11:356–365. https://doi.org/10.1016/j.fshw.2021.11.013
Ma JJ, Ma LY, Zhang H, Zhang ZQ, Wang YQ, Li K, Chen XM (2018b) Policosanol fabrication from insect wax and optimization by response surface methodology. PloS one 13. https://doi.org/10.1371/journal.pone.0197343
Malaiwong N, Chalorak P, Jattujan P, Manohong P, Niamnont N, Suphamungmee W, Sobhon P, Meemon K (2019) Anti-Parkinson activity of bioactive substances extracted from Holothuria leucospilota. Biomed Pharmacother 109:1967–1977. https://doi.org/10.1016/j.biopha.2018.11.063
Mao Q, Qin WZ, Zhang A, Ye N (2020) Recent advances in dopaminergic strategies for the treatment of Parkinson’s disease. Acta Pharmacol Sin 41:471–482. https://doi.org/10.1038/s41401-020-0365-y
Marques NF, Massari CM, Tasca CI (2019) Guanosine Protects Striatal Slices Against 6-OHDA-Induced Oxidative Damage, Mitochondrial Dysfunction, and ATP Depletion. Neurotox Res 35:475–483. https://doi.org/10.1007/s12640-018-9976-1
Mehra S, Sahay S, Maji SK (2019) α-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1867:890–908. https://doi.org/10.1016/j.bbapap.2019.03.001
Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87. https://doi.org/10.1146/annurev.neuro.28.061604.135718
Nasuti C, Brunori G, Eusepi P, Marinelli L, Ciccocioppo R, Gabbianelli R (2017) Early life exposure to permethrin: a progressive animal model of Parkinson’s disease. J Pharmacol Toxicol Methods 83:80–86. https://doi.org/10.1016/j.vascn.2016.10.003
Neef DW, Jaeger AM, Thiele DJ (2011) Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat Rev Drug Discovery 10:930–944. https://doi.org/10.1038/nrd3453
Offenburger SL, Gartner A (2018) 6-hydroxydopamine (6-OHDA) Oxidative Stress Assay for Observing Dopaminergic Neuron Loss in Caenorhabditis elegans. Bio Protoc 8. https://doi.org/10.21769/BioProtoc.3025.
Park HJ, Yadav D, Jeong DJ, Kim SJ, Bae MA, Kim JR, Cho KH (2019) Short-Term Consumption of Cuban Policosanol Lowers Aortic and Peripheral Blood Pressure and Ameliorates Serum Lipid Parameters in Healthy Korean Participants: Randomized, Double-Blinded, and Placebo-Controlled Study. Int J Environ Res Public Health 16. https://doi.org/10.3390/ijerph16050809
Pourkarimi E, Greiss S, Gartner A (2012) Evidence that CED-9/Bcl2 and CED-4/Apaf-1 localization is not consistent with the current model for C. elegans apoptosis induction. Cell Death Differ 19:406–415. https://doi.org/10.1038/cdd.2011.104
Rango M, Bresolin N (2018) Brain mitochondria aging and parkinson’s disease. Genes 9(5):250. https://doi.org/10.3390/genes9050250
Rashidi R, Ghorbani A, Rakhshandeh H, Mousavi SH (2021) Protective effect of Artemisia absinthium on 6-hydroxydopamine-induced toxicity in SH-SY5Y cell line. Avicenna J Phytomed 11:238–246
Raza C, Anjum R, Shakeel NUA (2019) Parkinson’s disease: Mechanisms, translational models and management strategies. Life Sci 226:77–90. https://doi.org/10.1016/j.lfs.2019.03.057
Renoudet VV, Costa-Mallen P, Hopkins E (2012) A diet low in animal fat and rich in N-hexacosanol and fisetin is effective in reducing symptoms of Parkinson’s disease. J Med Food 15:758–761. https://doi.org/10.1089/jmf.2012.0060
Rocha EM, De Miranda B, Sanders LH (2018) Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol Dis 109:249–257. https://doi.org/10.1016/j.nbd.2017.04.004
Rodriguez M, Snoek LB, De Bono M, Kammenga JE (2013) Worms under stress: C. elegans stress response and its relevance to complex human disease and aging. Trends Genet 29:367–374. https://doi.org/10.1016/j.tig.2013.01.010
Ruiperez V, Darios F, Davletov B (2010) Alpha-synuclein, lipids and Parkinson’s disease. Prog Lipid Res 49:420–428. https://doi.org/10.1016/j.plipres.2010.05.004
Salari S, Bagheri M (2019) In vivo, in vitro and pharmacologic models of Parkinson’s disease. Physiol Res 68:17–24. https://doi.org/10.33549/physiolres.933895
Sanchez J, Illnait J, Mas R, Mendoza S, Fernandez L, Mesa M, Vega H, Fernandez J, Reyes P, Ruiz D (2017) Long-term effect of policosanol on the functional recovery of non-cardioembolic ischemic stroke patients: A one year study. Rev Neurol 64:153–161. https://doi.org/10.33588/rn.6404.2016180
Sánchez López J, Fernández Travieso JC, Illnait Ferrer J, Fernández Dorta L, Mendoza Castaño S, Mas Ferreiro R, Mesa Angarica M, Reyes Suárez P (2018) Efectos del policosanol en la recuperación funcional de pacientes hipertensos con ictus isquémico no cardioembólico. Revista de Neurología 67:331–338. https://doi.org/10.33588/rn.6709.2018063
Segura-Aguilar J, Paris I, Munoz P, Ferrari E, Zecca L, Zucca FA (2014) Protective and toxic roles of dopamine in Parkinson’s disease. J Neurochem 129:898–915. https://doi.org/10.1111/jnc.12686
Sharma S, Trivedi S, Pandey T, Ranjan S, Trivedi M, Pandey R (2021) Wedelolactone Mitigates Parkinsonism Via Alleviating Oxidative Stress and Mitochondrial Dysfunction Through NRF2/SKN-1. Mol Neurobiol 58:65–77. https://doi.org/10.1007/s12035-020-02080-4
Teismann P, Schulz JB (2004) Cellular pathology of Parkinson’s disease: astrocytes, microglia and inflammation. Cell Tissue Res 318:149–161. https://doi.org/10.1007/s00441-004-0944-0
Urban N, Tsitsipatis D, Hausig F, Kreuzer K, Erler K, Stein V, Ristow M, Steinbrenner H, Klotz LO (2017) Non-linear impact of glutathione depletion on C. elegans life span and stress resistance. Redox Biol 11:502–515. https://doi.org/10.1016/j.redox.2016.12.003
Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, Nelson LM (2003) Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 157:1015–1022. https://doi.org/10.1093/aje/kwg068
Vanduyn N, Settivari R, Wong G, Nass R (2010) SKN-1/Nrf2 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of methylmercury toxicity. Toxicol Sci 118:613–624. https://doi.org/10.1093/toxsci/kfq285
Wang T, Liu YY, Wang X, Yang N, Zhu HB, Zuo PP (2010) Protective effects of octacosanol on 6-hydroxydopamine-induced Parkinsonism in rats via regulation of ProNGF and NGF signaling. Acta Pharmacol Sin 31:765–774. https://doi.org/10.1038/aps.2010.69
Wang ZD, Feng Y, Ma LY, Li X, Ding WF, Chen XM (2017) Hair growth promoting effect of white wax and policosanol from white wax on the mouse model of testosterone-induced hair loss. Biomed Pharmacother 89:438–446. https://doi.org/10.1016/j.biopha.2017.02.036
Wang HY, Jiao QP, Chen SY, Sheng J, Jiang H, Lu J, Zheng SB, Fang NY (2018) Efficacy and Safety of Policosanol Plus Fenofibrate Combination Therapy in Elderly Patients with Mixed Dyslipidemia: A Randomized, Controlled Clinical Study. Am J Med Sci 356:254–261. https://doi.org/10.1016/j.amjms.2018.06.014
Wang ZD, Feng Y, Sun L, Gan J, Li X, Ding WF, Chen XM (2021) Anti-androgenetic alopecia effect of policosanol from Chinese wax by regulating abnormal hormone levels to suppress premature hair follicle entry into the regression phase. Biomed Pharmacother 136:111241. https://doi.org/10.1016/j.biopha.2021.111241
Wang T, Liu Y, Yang N, Ji C, Chan P, Zuo P (2012) Anti-parkinsonian effects of octacosanol in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-treated mice. Neural Regen Res 7. https://doi.org/10.3969/j.issn.1673-5374
Yan N, Chai J, Lee ES, Gu L, Liu Q, He J, Wu JW, Kokel D, Li H, Hao Q, Xue D, Shi Y (2005) Structure of the CED-4-CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans. Nature 437:831–837. https://doi.org/10.1038/nature04002
Zhang K, Zhu S, Li J, Jiang T, Feng L, Pei J, Wang G, Ouyang L, Liu B (2021a) Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson’s disease. Acta Pharmaceutica Sinica B. https://doi.org/10.1016/j.apsb.2021.02.016
Zhang X, Ma CJ, Sun L, He Z, Feng Y, Li X, Gan J, Chen XM (2021b) Effect of policosanol from insect wax on amyloid beta-peptide-induced toxicity in a transgenic Caenorhabditis elegans model of Alzheimer’s disease. BMC Complement Med Ther 21:103. https://doi.org/10.1186/s12906-021-03278-2
Zhao JJ, Zhong QJ, Zhang JY, Li ZG, Hu YP, Dou WL, Wang H, Lu QW, Wu MZ (2021) Investigation on the production status in seed insects of Ericerus pela. Mod Agric Sci Technol 6:193–201. https://doi.org/10.3969/j.issn.1007-5739.2021.06.080
Zhou Y (1980) The History of Entomology in China. Xian Entomotaxonomia, Shanxi
Zou SW (1982) A History of Chinese Entomology. Science Press, Beijing
Acknowledgements
We would like to acknowledge Dr. Ding Aijun (Kunming University, Yunnan, China.) provided the C. elegans strains including N2, BZ555, and NL5901.
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This work was supported by grants from the Chinese Academy of Forestry (No. CAFYBB2019SZ005).
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Ma, C., Feng, Y., Li, X. et al. Potential Therapeutic Effects of Policosanol from Insect Wax on Caenorhabditis elegans Models of Parkinson’s Disease. J Neuroimmune Pharmacol 18, 127–144 (2023). https://doi.org/10.1007/s11481-022-10057-4
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DOI: https://doi.org/10.1007/s11481-022-10057-4