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

Abstract

Parkinson’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.

Calycosin Alleviates Paraquat-Induced Neurodegeneration by Improving Mitochondrial Functions and Regulating Autophagy in a Drosophila Model of Parkinson’s Disease

“…We used an environmental neurotoxin-induced Drosophila neurodegenerative model that recapitulates the locomotor behaviors and other pathological symptoms of human PD as a screening platform to find nutraceuticals with neuroprotective efficacy against PQ-induced neurotoxicity. Earlier studies reported that PQ (5 mM) exposure significantly decreases survival and impairs the locomotor abilities of Drosophila wild-type flies [ 28 , 33 , 40 ]. In the present study, we used only adult male flies due to their greater sensitivity to PQ-induced neurotoxicity at earlier stages than female flies, while the mating status of female flies showed a different feeding pattern.…”

“…Three to five-day-old male flies were starved for 6 h in only agar containing vials, and after that, all flies were transferred into agar, sucrose and 5 mM PQ with or without calycosin (100.0 µM) for 48 h. Control flies were transferred into those vials that contained only sucrose and agar. A 5-mM PQ concentration was selected for the study of neurotoxic effects in Drosophila, following earlier studies [ 28 , 33 , 40 ].…”

“…L-dopa, currently prescribed as the most commonly used medicine for PD treatment, was first extracted from the Vicia faba bean. In addition, other natural molecules produced from plants and microbes have been associated with decreased mortality and protective effects against toxin-induced neurodegeneration—for instance, fisetin, rapamycin, metformin, catalpol, gardenine-A, vasicinone, curcumin and its derivatives, quercetin and 7,8-dihydroxyflavone [ 24 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. However, the neuroprotective molecular mechanisms of the flavonoid compounds are yet not fully clear.…”

“…In the present study, we employed Drosophila melanogaster , which is a widely accepted PQ-induced PD model [ 11 , 12 , 28 , 33 ], as an in vivo screening platform to investigate the neuroprotective efficacy of natural compounds on PD. Plants produce several compounds, many of which interact with evolutionarily conserved signaling pathways, as these molecules evolved either with a common ancestor or in response to insect herbivory.…”

The Combination of Tradition and Future: Data-Driven Natural-Product-Based Treatments for Parkinson’s Disease

“…Considering these advantages, an increasing number of research has been focusing on improving PD treatments with natural products. In a recent study, for example, gardenin A has shown its role in neuroprotection against environmental-toxin-induced Parkinson's disease pathogenesis [13]. Another study by Haruka et al pointed out that sesaminol may increase Nrf2 expression and then activate the Nrf2-ARE signaling pathway and decrease the expression level of α-synuclein, indicating its preventative effect on PD [14].…”