Neuroprotective Effect of CR-777, a Glutathione Derivative of Withaferin A, Obtained through the Bioconversion of Withania somnifera (L.) Dunal Extract by the Fungus Beauveria bassiana.

Chérif Rabhi,Jamal Ouazzani,Guillaume Arcile,Géraldine Le Goff,Christian Da Costa Noble

doi:10.3390/molecules24244599

Chérif Rabhi, Jamal Ouazzani + Show 3 more

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https://doi.org/10.3390/molecules24244599

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Abstract

The bioconversion of Withania somnifera extract by the fungus Beauveria bassiana leads to cysteine and glutathione derivatives of withaferin A at the C-6 position. The compounds were purified and fully characterized by 1D-NMR, 2D-NMR, and HRMS analysis. The glutathione derivative CR-777 was evaluated as a neuroprotective agent from damage caused by different neurotoxins mimicking molecular symptoms in Parkinson´s disease (PD), including 1-methyl-4-phenylpyridinium (MPP+), 6-hydroxydopamine (6-OHDA), and α-synuclein (α-Syn). CR-777, at nanomolar concentrations, protected dopaminergic and cortical neurons. In 6-OHDA-treated neurons, CR-777 increased cell survival and neurite network and decreased the expression of α-Syn. Using specific inhibitors of cell toxicity signaling pathways and specific staining experiments, the observed role of CR-777 seemed to involve the PI3K/mTOR pathway. CR-777 could be considered as a protective agent against a large panel of neuronal stressors and was engaged in further therapeutic development steps.

Highlights

Neurodegenerative diseases include different pathologies such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)
Together with Bacopa monnieri and Emblica officinalis, was bioconverted by Beauveria bassiana to lead to a nutraceutical preparation called SNC1
Two new compounds were isolated from the biotransformed extracts of W. somnifera and fully characterized as the cysteine and glutathione conjugates of withaferin A

Summary

Introduction

Neurodegenerative diseases include different pathologies such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The neuron degeneration is multifactorial, including environmental, molecular, cellular, and genetic factors, and involves an increase in oxidative stress, impaired cell signaling and functions, deposition of aggregated proteins, and inflammation. Herbal ingredients and their constituents were extensively investigated for the prevention and treatment of AD [1] and PD [2,3]. Beyond neuroprotection [6,7], many activities were reported for Withania somnifera extracts or pure compounds, including antibacterial, anticancer, antidiabetic, cardioprotective, and anti-inflammatory properties [5]. Several patents on different compositions of plant extracts have been filed [8]; no single pharmacological compound has been developed to date

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