Prevention of MEK-ERK-1/2 hyper-activation underlines the neuroprotective effect of Glycyrrhiza glabra L. (Yashtimadhu) against rotenone-induced cellular and molecular aberrations

Yashtimadhu choorna (powder) is prepared from the dried root of Glycyrrhiza glabra L., commonly known as licorice. The Indian Ayurvedic system classifies Yashtimadhu as a Medhya Rasayana that can enhance brain function, improves memory, and possess neuroprotective functions, which can be used against neurodegenerative diseases like Parkinson's disease (PD). We aimed to decipher the neuroprotective effects of G. glabra L., i.e., Yashtimadhu, in a rotenone-induced PD model. Retinoic acid-differentiated IMR-32 cells were treated with rotenone (PD model) and Yashtimadhu, and were assessed for cellular toxicity, live-dead staining, cell cycle, oxidative stress, protein abundance, and kinase phosphorylation. Yashtimadhu conferred protection against rotenone-induced cytotoxicity, countered cell death, reduced expression of pro-apoptotic proteins (cleaved-caspases-9, and 3, cleaved-PARP, BAX, and BAK) and increased anti-apoptotic protein, BCL-2. Rotenone-induced cell cycle re-entry (G2/M transition), was negated by Yashtimadhu and was confirmed with PCNA levels. Yashtimadhu countered rotenone-mediated activation of mitochondrial proteins involved in oxidative stress, cytochrome-C, PDHA1, and HSP60. Inhibition of rotenone-induced ERK-1/2 hyperphosphorylation prevented activation of apoptosis, which was confirmed with MEK-inhibitor, highlighted the action of Yashtimadhu via ERK-1/2 modulation. We provide the evidence for neuroprotection conferred by G. glabra L. (Yashtimadhu) and its mechanism via inhibiting MEK-ERK-1/2 hyper-phosphorylation, prevention of mitochondrial stress, and subsequent prevention of apoptosis. The study highlights Yashtimadhu as a promising candidate with neuroprotective effects, the potential of which can be harnessed for identifying novel therapeutic targets. [Display omitted] •Glycyrrhiza glabra L. confers neuroprotection by preventing the rotenone-induced apoptosis via MEK-ERK-1/2 pathway.•Glycyrrhiza glabra L. also protects against rotenone-induced mitochondrial and oxidative stress.•Modulation of ERK-1/2 and regulation of cell cycle protects the neuronal cells from rotenone-induced mitotic catastrophe.