withaferin-a and Tauopathies

Ashwagandha-Withania somnifera (L.) Dunal, well known for its multipotent therapeutic properties has been used in Ayurveda for 3000 years. The plant with more than 50 active phytoconstituents is recognised for its anti-cancerous, anti-diabetic, anti-inflammatory, anti-microbial, and neurotherapeutic properties demonstrated in in vitro studies and chemically induced rodent models. Genetically targeted Parkinson's, Alzheimer's and other neurodegenerative disease models have been created in Drosophila and have been used to get mechanistic insight into the in vivo cellular events, and genetic pathways that underlie respective neurodegenerative condition. But hitherto, there aren't enough attempts made to capitalize the genetic potential of these disease models to validate the therapeutic efficacy of different reagents used in traditional medicine, in the context of specific disease-causing genetic mutations.. Drugs discovered using in vitro platforms might fail in several instances of clinical trials because of the genetic heterogeneity and variability in the physiological context found among the patients. Drosophila by virtue of its genetically regulated experimental potential forms an ideal in vivo model to validate the candidate reagents discovered in in vitro screens for their efficacy under specific genetic situations. Here we have used genetically induced α-synucleinopathy and tauopathy transgenic fly models to study the efficacy of Ashwagandha treatment, assessing cellular and behavioural parameters.. We have expressed the disease-causing human gene mutations in specific cell types of Drosophila using GAL4/UAS targeted expression system to create disease models. Human α-synuclein mutant (A30P) was expressed in dopaminergic neurons using Ddc-GAL4 driver strain to induce dopaminergic neurodegeneration and assayed for motor dysfunction. Human Tau. Lifespan assay shows that, Ashwagandha-root extract imparts an extended lifespan in male Drosophila flies which are intrinsically less stress resistant. Motor dysfunction caused due to human α-synuclein mutant protein expressed in dopaminergic neurons is greatly brought down. Further, Ashwagandha extract treatment significantly reduces Tau. We have carried out a multifaceted study which elucidates that Ashwagandha can serve as a comprehensive, phytotherapeutic formulation to combat neurodegeneration, targeting multiple causative genetically defective conditions.

Topics: alpha-Synuclein; Animals; Drosophila; Humans; Neurodegenerative Diseases; Plant Extracts; Tauopathies; Withania