Metabolomics analysis highlights Yashtimadhu (Glycyrrhiza glabra L.)‐mediated neuroprotection in a rotenone‐induced cellular model of Parkinson's disease by restoring the mTORC1‐AMPK1 axis in autophagic regulation

Abstract

Parkinson's disease (PD) is an age‐associated progressive neurodegenerative movement disorder, and its management strategies are known to cause complications with prolonged usage. We aimed to explore the neuroprotective mechanism of the Indian traditional medicine Yashtimadhu, prepared from the dried roots of Glycyrrhiza glabra L. (licorice) in the rotenone‐induced cellular model of PD. Retinoic acid–differentiated IMR‐32 cells were treated with rotenone (PD model) and Yashtimadhu extract. Mass spectrometry‐based untargeted and targeted metabolomic profiling was carried out to discover altered metabolites. The untargeted metabolomics analysis highlighted the rotenone‐induced dysregulation and Yashtimadhu‐mediated restoration of metabolites involved in the metabolism of nucleic acids, amino acids, lipids, and citric acid cycle. Targeted validation of citric acid cycle metabolites showed decreased α‐ketoglutarate and succinate with rotenone treatment and rescued by Yashtimadhu co‐treatment. The dysregulation of the citric acid cycle by rotenone‐induced energetic stress via dysregulation of the mTORC1‐AMPK1 axis was prevented by Yashtimadhu. Yashtimadhu co‐treatment restored rotenone‐induced ATG7‐dependent autophagy and eventually caspases‐mediated cell death. Our analysis links the metabolic alterations modulating energy stress and autophagy, which underlies the Yashtimadhu‐mediated neuroprotection in the rotenone‐induced cellular model of PD.

Comparative metabolomics and network pharmacology analysis reveals shared neuroprotective mechanisms of Bacopa monnieri (L.) Wettst and Centella asiatica (L.) Urb

“…We further explored the effect of B. monnieri and C. asiatica metabolites on the human system using bioinformatics approaches to identify and predict proteins interacting with B. monnieri and C. asiatica metabolites. We identi ed hundreds of proteins interacting with the identi ed metabolites, encompassing important cellular functions such as cell cycle, autophagy, mitophagy, and apoptosis, which are dysregulated in neurodegenerative diseases [33,36,52]. Apart from the cellular functions, signaling mediated by neurotrophin, dopamine, serotonin, and acetylcholine was predicted from our analysis, which .…”

“…IMR32 cells in the density of 1 x 10⁴ cells per well were seeded in 1X collagen-coated 6-well plates and were differentiated for seven days using 10 µM retinoic acid. In the Parkinson's disease model, the cells were treated with rotenone (100 nM) [33], rotenone (100 nM) + B. monnieri /C. asiatica extract (100 µg/ml), B. monnieri / C. asiatica extract alone (100 µg/ml).…”

Real-world Chinese herbal medicine for Parkinson's disease: a hospital-based retrospective analysis of electronic medical records

“…Water extracts of Glycyrrhiza uralensis Fisch. ( gan cao ) demonstrated neuroprotective effects via regulating ERK-1/2 pathways and the mTORC1-AMPK1 axis, as well as inhibiting MAO-2 action in in vitro studies (Karthikkeyan et al, 2021 , 2022 ; Ramadan et al, 2022 ). Its active compounds like Licopyranocoumarin, glycyrurol , and isoliquiritigenin , exerted anti-apoptosis against oxidative stress (Hwang and Chun, 2012 ; Fujimaki et al, 2014 ).…”

Protective effect of Glycyrrhiza glabra L. root (licorice) extract against severe acute pancreatitis-induced acute lung injury via suppressing autophagy and inflammation

“…Beclin-1 a multi domain protein plays a significant role in the cross-regulation of autophagy and apoptosis. Moreover, caspases participate in inflammation and cell death; caspases are shown to interact and cause cleavage of several autophagy proteins including beclin-1 and reduce their autophagic function (28).…”

“…Thus, phytochemical compounds acting as modulators of beclin-1 could be therapeutically beneficial in AP (27). Moreover, TLR-4 activation triggered apoptosis via a high caspase-3 activity (22), while licorice caused a significant reduction in caspase-3 activity (28). Thus, it is supposed that licorice extract protected the pancreas from autophagic impairment and protected pancreatic acinar cells from injury.…”