Melatonin Increases Life Span, Restores the Locomotor Activity, and Reduces Lipid Peroxidation (LPO) in Transgenic Knockdown Parkin Drosophila melanogaster Exposed to Paraquat or Paraquat/Iron.
Parkinson's disease (PD) is a complex progressive neurodegenerative disorder involving impairment of bodily movement caused by the specific destruction of dopaminergic (DAergic) neurons. Mounting evidence suggests that PD might be triggered by an interplay between environmental neurotoxicants (e.g., paraquat, PQ), heavy metals (e.g., iron), and gene alterations (e.g., PARKIN gene). Unfortunately, there are no therapies currently available that protect, slow, delay, or prevent the progression of PD. Melatonin (Mel, N-acetyl-5-methoxy tryptamine) is a natural hormone with pleiotropic functions including receptor-independent pathways which might be useful in the treatment of PD. Therefore, as a chemical molecule, it has been shown that Mel prolonged the lifespan and locomotor activity, and reduced lipid peroxidation (LPO) in wild-type Canton-S flies exposed to PQ, suggesting antioxidant and neuroprotective properties. However, it is not yet known whether Mel can protect or prevent the genetic model parkin deficient in flies against oxidative stress (OS) stimuli. Here, we show that Mel (0.5, 1, 3 mM) significantly extends the life span and locomotor activity of TH > parkin-RNAi/ + Drosophila melanogaster flies (> 15 days) compared to untreated flies. Knock-down (K-D) parkin flies treated with PQ (1 mM) or PQ (1 mM)/iron (1 mM) significantly diminished the survival index and climbing abilities (e.g., 50% of flies were dead and locomotor impairment by days 4 and 3, respectively). Remarkably, Mel reverted the noxious effect of PQ or PQ/iron combination in K-D parkin. Indeed, Mel protects TH > parkin-RNAi/ + Drosophila melanogaster flies against PQ- or PQ/iron-induced diminish survival, locomotor impairment, and LPO (e.g., 50% of flies were death and locomotor impairment by days 6 and 9, respectively). Similarly, Mel prevented K-D parkin flies against both PQ and PQ/iron. Taken together, these findings suggest that Mel can be safely used as an antioxidant and neuroprotectant agent against OS-stimuli in selective individuals at risk to suffer early-onset Parkinsonism and PD.
Ortega-Arellano HF
，Jimenez-Del-Rio M
，Velez-Pardo C
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Acute exposure of Drosophila melanogaster to paraquat causes oxidative stress and mitochondrial dysfunction.
Paraquat (PQ; 1, 1'-dimethyl-4-4'-bipyridinium), an herbicide and model neurotoxicant, is identified to be one of the prime risk factors in Parkinson's disease (PD). In the Drosophila system, PQ is commonly used to measure acquired resistance against oxidative stress (PQ resistance test). Despite this, under acute PQ exposure, data on the oxidative stress response and associated impact on mitochondria among flies is limited. Accordingly, in this study, we measured markers of oxidative stress and mitochondrial dysfunctions among adult male flies (8-10 days old) exposed to varying concentrations of PQ (10, 20, and 40 mM in 5% sucrose solution) employing a conventional filter disc method for 24 h. PQ exposure resulted in significant elevation in the levels of oxidative stress biomarkers (malondialdehyde: 43% increase: hydroperoxide: 32-39% increase), with concomitant enhancement in reduced glutathione and total thiol levels in cytosol. Higher activity of antioxidant enzymes were also evident along with increased free iron levels. Furthermore, PQ exposure caused a concentration-dependent increase in mitochondrial superoxide generation and activity of manganese-superoxide dismutase (Mn-SOD). The activity levels of complex I-III, complex II-III, and Mg+2 adinosine triphosphatase (ATPase) were also decreased significantly. A robust diminution in the activity of succinate dehydrogenase and moderate decline in the citrate synthase activity suggested a specific effect on citric acid cycle enzymes. Collectively, these data suggest that acute PQ exposure causes significant oxidative stress and mitochondrial dysfunction among flies in vivo. It is suggested that in various experimental settings, while conducting the "PQ resistance stress test" incorporation of selected biochemical end points is likely to enhance the quality of the data.
Hosamani R
，Muralidhara
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