Abstract
The present study was aimed at characterizing the effects of Withania somnifera (Wse) and Mucuna pruriens (Mpe) on a Drosophila melanogaster model for Amyotrophic Lateral Sclerosis (ALS). In particular, the effects of Wse and Mpe were assessed following feeding the flies selectively overexpressing the wild human copper, zinc-superoxide dismutase (hSOD1-gain-of-function) in Drosophila motoneurons. Although ALS-hSOD1 mutants showed no impairment in life span, with respect to GAL4 controls, the results revealed impairment of climbing behaviour, muscle electrophysiological parameters (latency and amplitude of ePSPs) as well as thoracic ganglia mitochondrial functions. Interestingly, Wse treatment significantly increased lifespan of hSDO1 while Mpe had not effect. Conversely, both Wse and Mpe significantly rescued climbing impairment, and also latency and amplitude of ePSPs as well as failure responses to high frequency DLM stimulation. Finally, mitochondrial alterations were any more present in Wse- but not in Mpe-treated hSOD1 mutants. Hence, given the role of inflammation in the development of ALS, the high translational impact of the model, the known anti-inflammatory properties of these extracts, and the viability of their clinical use, these results suggest that the application of Wse and Mpe might represent a valuable pharmacological strategy to counteract the progression of ALS and related symptoms.
Highlights
SOD1 can seed misfolding and aggregation of endogenous wild-type SOD1 and transfer from cell to cell causing the intercellular transmission of disease through the central nervous system, a propagation mechanism similar to prion replication and spreading[9,10]
To previous results, obtained with fly models of Parkinson’s disease[18,19], the human SOD1 (hSOD1) mutants were treated with Withania somnifera (Wse) or Mucuna pruriens (Mpe) at 0.1% w/w in their standard diet starting from larvae stage (L+/A+) or as adults only (L−/A+)
In agreement with Watson et al.[21] the results of the present study disclosed that the survival curves of flies overexpressing hSOD1-GOF in motoneurons were not significantly impaired with respect to GAL4 control flies
Summary
SOD1 can seed misfolding and aggregation of endogenous wild-type SOD1 and transfer from cell to cell causing the intercellular transmission of disease through the central nervous system, a propagation mechanism similar to prion replication and spreading[9,10]. ® their progression, with the partial exception of the antiglutamatergic Riluzole In this context, given the results obtained in two different Drosophila models of Parkinson disease (PD-LRRK2-LOF and PD-PINK1B9-LOF) with the application of two methanolic extracts of parts of the medicinal plants, Withania somnifera and Mucuna pruriens widely used in the Ayurvedic medicine[17,18,19,22,23,24] for their potential effects on treating many central nervous system disorders, we deemed to investigate their effects on ALS symptoms. Based on the observations (1) that the PD-LRRK2 and ALS-SOD1 diseases share common oxidative stress- and neuroinflammation-based mechanisms and (2) that both Withania somnifera and Mucuna pruriens are endowed with potent anti-oxidative and anti-inflammatory properties, the results of the present study are expected to provide new data on the pathophysiology of ALS models and to suggest possible new vistas in the inflammatory, oxidative stress, genetic roles correlated to this neurodegeneration. In the context of current knowledge about the mechanism of action of these drugs, even if they do not regard ALS, a few references provide insight on the mechanism by which these compounds exert their anti-inflammatory effects[28,29]
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