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 RabhiGuillaume ArcileGéraldine Le GoffChristian Da Costa NobleJamal OuazzaniPublished in: Molecules (Basel, Switzerland) (2019)
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.
Keyphrases
- oxidative stress
- magnetic resonance
- high resolution
- spinal cord
- signaling pathway
- cell proliferation
- poor prognosis
- cerebral ischemia
- single cell
- cell therapy
- anti inflammatory
- epithelial mesenchymal transition
- bone marrow
- solid state
- long non coding rna
- subarachnoid hemorrhage
- solid phase extraction
- newly diagnosed
- high resolution mass spectrometry