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.
Highlights
Parkinson’s disease is an age-associated neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons from the midbrain
There is an urgent need for novel advances in PD therapy that can target the underlying pathways associated with the disease onset and progression
Our data show that pretreatment with the flavonoid, GA, significantly improves survival, mobility defects, and dopaminergic neuron loss against PQ-induced neurotoxicity in Drosophila
Summary
Parkinson’s disease is an age-associated neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons from the midbrain. Our findings reveal a molecular mechanistic insight into GardeninA-mediated neuroprotection against environmental toxin-induced Parkinson’s disease pathogenesis for novel therapeutic intervention. PQ has been shown to induce dysregulated inflammatory responses related to neuronal cell death[6] Both oxidative stress and neuroinflammation have been associated with PD pathogenesis in both mammalian and Drosophila models[9]. Several studies focus on evaluating the neuroprotective effects in cell culture models using super-physiological concentrations of phytochemicals, which mostly translate to poor clinical outcomes[28]. Another concern regarding the use of natural products, especially flavonoids as therapeutics is their poor bioavailability[29]. There is a need to evaluate the neuroprotective effects of natural products at pharmacologically relevant concentrations in the context of a living organism
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