Neuroprotective Effect of Withaferin Derivatives toward MPP⁺ and 6-OHDA Toxicity to Dopaminergic Neurons

Parkinson's disease is a neurodegenerative proteinopathy that primarily affects mesencephalic dopaminergic neurons. This dopaminergic depletion can be phenotypically reproduced in various experimental models through the administration of two neurotoxins: N-methyl-4-phenylpyridinium (MPP⁺) and 6-hydroxydopamine (6-OHDA). The mechanisms underlying the cell death processes induced by these toxins remain a subject of debate. In this context, studies suggest that oxidative-stress-related processes may contribute to the dysfunction and death of dopaminergic neurons. Therefore, investigating pharmacological compounds that can counteract these processes remains crucial for developing therapeutic strategies targeting these neuropathological mechanisms. Withania somnifera (L.) Dunal, commonly known as ashwagandha, is a plant whose roots are used in Ayurvedic medicine to treat various ailments, including those affecting the central nervous system. The active compound Withaferin-A (WFA), a steroid lactone from the withanolide group, is reported to possess antioxidant properties. In this study, we explored the potential neuroprotective effects of WFA and two of its molecular derivatives, cr-591 and cr-777, which contain, respectively, an additional cysteine or glutathione chemical group, known for their antiradical properties. We demonstrated that WFA and its two derivatives, cr-591 and cr-777, protect the integrity and function of dopaminergic neurons exposed to the neurotoxins MPP⁺ and 6-OHDA both in vitro, using primary mesencephalic neuron cultures from rodents, and in vivo, using the nematode Caenorhabditis elegans.