Neuroprotective Potential of Glycyrrhizic Acid in Ischemic Stroke: Mechanisms and Therapeutic Prospects

Abstract

Background/Objectives: Ischemic stroke is a leading cause of disability and mortality worldwide, with current therapies limited in addressing its complex pathophysiological mechanisms, such as inflammation, oxidative stress, apoptosis, and impaired autophagy. Glycyrrhizic acid (GA), a bioactive compound from licorice (Glycyrrhiza glabra L.), has demonstrated neuroprotective properties in preclinical studies. This review consolidates current evidence on GA's pharmacological mechanisms and assesses its potential as a therapeutic agent for ischemic stroke. Methods: This review examines findings from recent preclinical studies and reviews on GA's neuroprotective effects, focusing on its modulation of inflammation, oxidative stress, apoptosis, and autophagy. Studies were identified from major scientific databases, including PubMed, Web of Science, and Embase, covering research from January 2000 to August 2024. Results: GA has demonstrated significant neuroprotective effects through the modulation of key pathways, including HMGB1/TLR4/NF-κB and Keap1/Nrf2, thereby reducing neuroinflammation, oxidative stress, and apoptosis. Additionally, GA promotes autophagy and modulates immune responses, suggesting it could serve as an adjunct therapy to enhance the efficacy and safety of existing treatments, such as thrombolysis. Conclusions: Current findings underscore GA's potential as a multi-targeted neuroprotective agent in ischemic stroke, highlighting its anti-inflammatory, antioxidant, and anti-apoptotic properties. However, while preclinical data are promising, further clinical trials are necessary to validate GA's therapeutic potential in humans. This review provides a comprehensive overview of GA's mechanisms of action, proposing directions for future research to explore its role in ischemic stroke management.

Keywords: Glycyrrhiza glabra; HMGB1; Keap1/Nrf2; apoptosis; autophagy; cerebral ischemia-reperfusion injury; glycyrrhizic acid; ischemic stroke; neuroprotection; oxidative stress.

Figure 1

Structural configurations of glycyrrhizic acid stereoisomers. (a) 18α-Glycyrrhizic Acid: The α stereoisomer of glycyrrhizic acid, featuring a specific spatial arrangement around the 18th carbon atom. (b) 18β-Glycyrrhizic Acid: The β stereoisomer, which is the predominant and biologically active form found in licorice root. Glycyrrhizic acid generally refers to this 18β form, known for its anti-inflammatory, antiviral, and hepatoprotective properties. Structural diagrams were downloaded from PubChem.

Figure 2

PRISMA flow diagram illustrating the study selection process.

Figure 3

Schematic illustration showing the anti-inflammatory and antioxidant effects of GA. On the left, GA inhibits the binding of HMGB1 to TLR4 and RAGE receptors, blocking downstream signaling cascades such as MyD88/TRAF6 and NF-κB activation, thereby reducing pro-inflammatory cytokine production. On the right, GA activates the Keap1/Nrf2 pathway, leading to increased expression of antioxidant enzymes (e.g., HO-1 and SOD), which reduce ROS and mitigate oxidative stress. Red T-shapes represent the inhibition of molecule expression, red and black arrows represent the promotion of molecule expression, and dashed black arrows indicate molecules with potential promotive influence.

Figure 4

Schematic representation of GA’s role in regulating apoptosis and autophagy. On the left, GA inhibits mitochondrial cytochrome c release and caspase-3 activation by modulating the Bax/Bcl-2 ratio, thus reducing neuronal apoptosis. On the right, GA promotes autophagy via the Keap1/Nrf2 and PINK1/Parkin pathway, facilitating the clearance of damaged mitochondria and reducing oxidative stress, contributing to enhanced neuronal survival. Red and black T-shapes represent the inhibition of molecule expression, red and black arrows indicate the promotion of molecule expression, and dotted red arrows represent molecules that may promote additional effects.