GardeninA confers neuroprotection against environmental toxin in a Drosophila model of Parkinson’s disease

Communications Biology - Tập 4 Số 1
Urmila Maitra1, Thomas C. Harding1, Qiaoli Liang2, Łukasz Cieśla1
1Department of Biological Sciences, University of Alabama, 2320 Science and Engineering Complex, Tuscaloosa, AL, 35487-0344, USA
2Mass Spectrometry Facility, Department of Chemistry and Biochemistry, University of Alabama, 2004 Shelby Hall, Tuscaloosa, AL, 35487-0336, USA

Tóm tắt

AbstractParkinson’s disease is an age-associated neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons from the midbrain. Epidemiological studies have implicated exposures to environmental toxins like the herbicide paraquat as major contributors to Parkinson’s disease etiology in both mammalian and invertebrate models. We have employed a paraquat-induced Parkinson’s disease model in Drosophila as an inexpensive in vivo platform to screen therapeutics from natural products. We have identified the polymethoxyflavonoid, GardeninA, with neuroprotective potential against paraquat-induced parkinsonian symptoms involving reduced survival, mobility defects, and loss of dopaminergic neurons. GardeninA-mediated neuroprotection is not solely dependent on its antioxidant activities but also involves modulation of the neuroinflammatory and cellular death responses. Furthermore, we have successfully shown GardeninA bioavailability in the fly heads after oral administration using ultra-performance liquid chromatography and mass spectrometry. Our findings reveal a molecular mechanistic insight into GardeninA-mediated neuroprotection against environmental toxin-induced Parkinson’s disease pathogenesis for novel therapeutic intervention.

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Tài liệu tham khảo

Heemels, M. T. Neurodegenerative diseases. Nature 539, 179 (2016).

Gooch, C. L., Pracht, E. & Borenstein, A. R. The burden of neurological disease in the United States: a summary report and call to action. Ann. Neurol. 81, 479–484 (2017).

Mhyre, T. R., Boyd, J. T., Hamill, R. W. & Maguire-Zeiss, K. A. Parkinson’s disease. Subcell. Biochem. 65, 389–455 (2012).

Ratner, M. H., Farb, D. H., Ozer, J., Feldman, R. G. & Durso, R. Younger age at onset of sporadic Parkinson’s disease among subjects occupationally exposed to metals and pesticides. Interdiscip. Toxicol. 7, 123–133 (2014).

Tanner, C. M. et al. Rotenone, paraquat, and Parkinson’s disease. Environ. Health Perspect. 119, 866–872 (2011).

Maitra, U., Scaglione, M. N., Chtarbanova, S. & O’Donnell, J. M. Innate immune responses to paraquat exposure in a Drosophila model of Parkinson’s disease. Sci. Rep. 9, 12714 (2019).

Duty, S. & Jenner, P. Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br. J. Pharm. 164, 1357–1391 (2011).

Stykel, M. G. et al. Nitration of microtubules blocks axonal mitochondrial transport in a human pluripotent stem cell model of Parkinson’s disease. FASEB J. 32, 5350–5364 (2018).

Schain, M. & Kreisl, W. C. Neuroinflammation in neurodegenerative disorders—a review. Curr. Neurol. Neurosci. Rep. 17, 25 (2017).

Maitra, U. & Ciesla, L. Using Drosophila as a platform for drug discovery from natural products in Parkinson’s disease. Medchemcomm 10, 867–879 (2019).

Bondonno, N. P. et al. Flavonoid intake is associated with lower mortality in the Danish Diet Cancer and Health Cohort. Nat. Commun. 10, 3651 (2019).

Shishtar, E., Rogers, G. T., Blumberg, J. B., Au, R. & Jacques, P. F. Long-term dietary flavonoid intake and risk of Alzheimer disease and related dementias in the Framingham Offspring Cohort. Am. J. Clin. Nutr. https://doi.org/10.1093/ajcn/nqaa079 (2020).

Lee, J., Jo, D. G., Park, D., Chung, H. Y. & Mattson, M. P. Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: focus on the nervous system. Pharm. Rev. 66, 815–868 (2014).

Howitz, K. T. & Sinclair, D. A. Xenohormesis: sensing the chemical cues of other species. Cell 133, 387–391 (2008).

Antioxidants Market by Type (Natural (Vitamin A, Vitamin B, Vitamin C, and Rosemary Extract), Synthetic (Butylated Hydroxyanisole, Butylated Hydroxytoluene, and Others)—Global Opportunity Analysis and Industry Forecast, 2014–2022, https://www.alliedmarketresearch.com/anti-oxidants-market (2016).

Baur, J. A. & Sinclair, D. A. What is xenohormesis? Am. J. Pharm. Toxicol. 3, 152–159 (2008).

Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 83, 770–803 (2020).

Rabey, J. M. et al. Broad bean (Vicia faba) consumption and Parkinson’s disease. Adv. Neurol. 60, 681–684 (1993).

Cassani, E. et al. Mucuna pruriens for Parkinson’s disease: low-cost preparation method, laboratory measures and pharmacokinetics profile. J. Neurol. Sci. 365, 175–180 (2016).

Reichmann, H. et al. Ergoline and non-ergoline derivatives in the treatment of Parkinson’s disease. J. Neurol. 253, IV36–IV38 (2006). Suppl 4.

Yang, S. et al. Curcumin protects dopaminergic neuron against LPS induced neurotoxicity in primary rat neuron/glia culture. Neurochem. Res. 33, 2044–2053 (2008).

Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).

Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018).

Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018).

Zhang, P. et al. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019).

Patil, S. P., Jain, P. D., Ghumatkar, P. J., Tambe, R. & Sathaye, S. Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience 277, 747–754 (2014).

Wang, L. Y. et al. Catalpol exerts a neuroprotective effect in the MPTP mouse model of Parkinson’s disease. Front. Aging Neurosci. 11, 316 (2019).

Chiu, S. P. et al. Neurotrophic action of 5-hydroxylated polymethoxyflavones: 5-demethylnobiletin and gardenin A stimulate neuritogenesis in PC12 cells. J. Agric. Food Chem. 61, 9453–9463 (2013).

Thilakarathna, S. H. & Rupasinghe, H. P. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 5, 3367–3387 (2013).

Alonso-Castro, A. J. et al. Evaluation of the neuropharmacological effects of Gardenin A in mice. Drug Dev. Res. https://doi.org/10.1002/ddr.21659 (2020).

Chaudhuri, A. et al. Interaction of genetic and environmental factors in a Drosophila parkinsonism model. J. Neurosci. 27, 2457–2467 (2007).

Camus, M. F., Huang, C. C., Reuter, M. & Fowler, K. Dietary choices are influenced by genotype, mating status, and sex in Drosophila melanogaster. Ecol. Evol. 8, 5385–5393 (2018).

Blesa, J., Trigo-Damas, I., Quiroga-Varela, A. & Jackson-Lewis, V. R. Oxidative stress and Parkinson’s disease. Front. Neuroanat. 9, 91 (2015).

Brunetti, C., Di Ferdinando, M., Fini, A., Pollastri, S. & Tattini, M. Flavonoids as antioxidants and developmental regulators: relative significance in plants and humans. Int. J. Mol. Sci. 14, 3540–3555 (2013).

Cuadrado, A. et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18, 295–317 (2019).

Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8, 382–397 (2009).

Hancock, D. B., Martin, E. R., Vance, J. M. & Scott, W. K. Nitric oxide synthase genes and their interactions with environmental factors in Parkinson’s disease. Neurogenetics 9, 249–262 (2008).

Xiong, Z. K. et al. Excessive levels of nitric oxide in rat model of Parkinson’s disease induced by rotenone. Exp. Ther. Med 9, 553–558 (2015).

Inamdar, A. A., Chaudhuri, A. & O’Donnell, J. The protective effect of minocycline in a paraquat-induced Parkinson’s disease model in Drosophila is modified in altered genetic backgrounds. Parkinson’s Dis. 2012, 938528 (2012).

Liberatore, G. T. et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat. Med. 5, 1403–1409 (1999).

Ajjuri, R. R. & O’Donnell, J. M. Novel whole-tissue quantitative assay of nitric oxide levels in Drosophila neuroinflammatory response. J. Vis. Exp. https://doi.org/10.3791/50892 (2013).

Khan, S. et al. Implication of caspase-3 as a common therapeutic target for multineurodegenerative disorders and its inhibition using nonpeptidyl natural compounds. Biomed. Res. Int. 2015, 379817 (2015).

Troy, C. M. & Jean, Y. Y. Caspases: therapeutic targets in neurologic disease. Neurotherapeutics 12, 42–48 (2015).

Shukla, A. K. et al. Heat shock protein-70 (Hsp-70) suppresses paraquat-induced neurodegeneration by inhibiting JNK and caspase-3 activation in Drosophila model of Parkinson’s disease. PLoS ONE 9, e98886 (2014).

Das, A., Banik, N. L. & Ray, S. K. Flavonoids activated caspases for apoptosis in human glioblastoma T98G and U87MG cells but not in human normal astrocytes. Cancer 116, 164–176 (2010).

White, J. B. et al. Some natural flavonoids are competitive inhibitors of Caspase-1, −3 and −7 despite their cellular toxicity. Food Chem. 131, 1453–1459 (2012).

Maher, P. The potential of flavonoids for the treatment of neurodegenerative diseases. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20123056 (2019).

Tran, J., Anastacio, H. & Bardy, C. Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells. NPJ Parkinsons Dis. 6, 8 (2020).

During, A. & Larondelle, Y. The O-methylation of chrysin markedly improves its intestinal anti-inflammatory properties: Structure-activity relationships of flavones. Biochem. Pharm. 86, 1739–1746 (2013).

Cassar, M. et al. A dopamine receptor contributes to paraquat-induced neurotoxicity in Drosophila. Hum. Mol. Genet. 24, 197–212 (2015).

Purisai, M. G. et al. Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiol. Dis. 25, 392–400 (2007).

Grosso, C., Valentao, P., Ferreres, F. & Andrade, P. B. The use of flavonoids in central nervous system disorders. Curr. Med. Chem. 20, 4694–4719 (2013).

Yang, W. L., Chen, S. Y., Ho, C. Y. & Yen, G. C. Citrus flavonoids suppress IL-5 and ROS through distinct pathways in PMA/ionomycin-induced EL-4 cells. Food Funct. 11, 824–833 (2020).

Lamming, D. W., Wood, J. G. & Sinclair, D. A. Small molecules that regulate lifespan: evidence for xenohormesis. Mol. Microbiol. 53, 1003–1009 (2004).

Beher, D. et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem. Biol. Drug Des. 74, 619–624 (2009).

Soccio, M., Laus, M. N., Alfarano, M. & Pastore, D. Measuring activity of native plant sirtuins—the wheat mitochondrial model. Front. Plant Sci. 9, 961 (2018).

Silverman, N. & Maniatis, T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev. 15, 2321–2342 (2001).

Tansey, M. G. & Goldberg, M. S. Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 37, 510–518 (2010).

Hunot, S. et al. Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with parkinson disease. Proc. Natl Acad. Sci. USA 94, 7531–7536 (1997).

Kounatidis, I. et al. NF-kappaB immunity in the brain determines fly lifespan in healthy aging and age-related neurodegeneration. Cell Rep. 19, 836–848 (2017).

Flood, P. M. et al. Transcriptional factor NF-κB as a target for therapy in Parkinson’s disease. Parkinsons Dis. 2011, 216298 (2011).

Wardyn, J. D., Ponsford, A. H. & Sanderson, C. M. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem. Soc. Trans. 43, 621–626 (2015).

Lee, Y. Y. et al. Anti-inflammatory and antioxidant mechanism of tangeretin in activated microglia. J. Neuroimmune Pharm. 11, 294–305 (2016).

Somboon, T. et al. Methyl jasmonate and cyclodextrin-mediated defense mechanism and protective effect in response to paraquat-induced stress in peanut hairy root. Phytochemistry 163, 11–22 (2019).

Hasanuzzaman, M. et al. Exogenous nitric oxide pretreatment protects Brassica napus L. seedlings from paraquat toxicity through the modulation of antioxidant defense and glyoxalase systems. Plant Physiol. Biochem. 126, 173–186 (2018).

Muhammad Kamran Qureshi, N. S., Tsanko, S. Gechev. & Jacques, Hille. The zinc finger protein ZAT11 modulates paraquat-induced programmed cell death in Arabidopsis thaliana. Acta Physiol. Plant 35, 1863–1871 (2013).

Delledonne, M., Xia, Y., Dixon, R. A. & Lamb, C. Nitric oxide functions as a signal in plant disease resistance. Nature 394, 585–588 (1998).

Nurnberger, T., Brunner, F., Kemmerling, B. & Piater, L. Innate immunity in plants and animals: striking similarities and obvious differences. Immunol. Rev. 198, 249–266 (2004).

Stafford, H. A. Flavonoid evolution: an enzymic approach. Plant Physiol. 96, 680–685 (1991).

Goyal, L., McCall, K., Agapite, J., Hartwieg, E. & Steller, H. Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function. Embo J. 19, 589–597 (2000).

Qiao, C. et al. Caspase-1 deficiency alleviates dopaminergic neuronal death via inhibiting caspase-7/AIF pathway in MPTP/p mouse model of Parkinson’s disease. Mol. Neurobiol. 54, 4292–4302 (2017).

Shukla, A. K. et al. Mutation in Drosophila methuselah resists paraquat induced Parkinson-like phenotypes. Neurobiol. Aging 35, 2419.e2411–2419.e2416 (2014).

Hartmann, A. et al. Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson’s disease, but pathway inhibition results in neuronal necrosis. J. Neurosci. 21, 2247–2255 (2001).

Rahul, Naz, F., Jyoti, S. & Siddique, Y. H. Effect of kaempferol on the transgenic Drosophila model of Parkinson’s disease. Sci. Rep. 10, 13793 (2020).

Cabrera, J. et al. Gardenin B-induced cell death in human leukemia cells involves multiple caspases but is independent of the generation of reactive oxygen species. Chem. Biol. Interact. 256, 220–227 (2016).

Zhang, J. et al. Identification of metabolites of gardenin A in rats by combination of high-performance liquid chromatography with linear ion trap-Orbitrap mass spectrometer based on multiple data processing techniques. Biomed. Chromatogr. 29, 379–387 (2015).

Baell, J. & Walters, M. A. Chemistry: chemical con artists foil drug discovery. Nature 513, 481–483 (2014).

Frantz, S. Drug discovery: playing dirty. Nature 437, 942–943 (2005).

Yang, K., Bai, H., Ouyang, Q., Lai, L. & Tang, C. Finding multiple target optimal intervention in disease-related molecular network. Mol. Syst. Biol. 4, 228 (2008).