Therapeutic potential of glycyrrhizin in nervous system diseases

To the Editor: Nervous system diseases among are leading causes of disability and death, with current small-molecule treatments mostly alleviating symptoms rather than offering cures. Natural products and dietary supplements, with their minimal side effects and properties like antioxidation and anti-inflammation, present promising new therapeutic avenues. Glycyrrhizin, a triterpenoid glycoside containing glycyrrhetinic acid (also known as glycyrrhizic acid or glycyrrhizinic acid), is the main bioactive component found in the dried roots and rhizomes of the licorice plant [Supplementary Figure 1, http://links.lww.com/CM9/C602]. Glycyrrhizin was approved by the U.S. Food and Drug Administration in 2014 as a natural sweetener and is widely used in food. Glycyrrhizin is currently considered an inhibitor of high-mobility group protein-1 (HMGB1) and can bind directly to HMGB1 by interacting with two shallow concave surfaces formed by the two arms of both high-mobility group (HMG) boxes.^[1] HMGB1 is a nuclear protein with a stable nucleic acid structure produced by activated innate immune cells, which in turn interacts with toll-like receptors (TLRs) to promote the production and release of various pro-inflammatory factors, playing an integral role in inflammation-mediated nervous system diseases.

Studies demonstrate glycyrrhizin’s beneficial effects across various neurological disorders, including cerebrovascular diseases, epilepsy, traumatic injuries, neurodegenerative diseases, mood disorders, and diabetic neuropathy (DN).^[2] Its broad pharmacological activity and few side effects identify it as a promising neuroprotective agent.

Cerebrovascular diseases include stroke, the most common type, alongside cerebrovascular atherosclerosis, cerebral aneurysm, and subarachnoid hemorrhage (SAH). Excessive glutamate can trigger neuronal death during ischemic stroke. Glycyrrhizin binds directly to the HMGB1 secreted by astrocytes, promoting the reuptake and clearance of glutamate, thereby protecting brain cells from damage. Glycyrrhizin can also induce apoptosis and ferroptosis in nerve cells by suppressing multiple signaling pathways, such as the HMGB1/toll-like receptor 4 (TLR4)/interleukin 17A (IL-17A) and HMGB1/glutathione peroxidase 4 (GPX4) signaling pathways, as well as by reducing inflammation and oxidative stress, thus improving brain function. Moreover, glycyrrhizin protects against hemorrhagic transformation (HT) during tissue plasminogen activator (t-PA) treatment of ischemic stroke by inhibiting the peroxynitrite (ONOO⁻)/HMGB1/toll-like receptor 2 (TLR2) signaling cascade. In neonatal hypoxic-ischemic brain injury (HIBI), glycyrrhizin alleviates neurodamage and behavioral disorders, regulates M1/M2 microglial cell polarization, and exerts neuroprotective effects. In SAH, glycyrrhizin suppresses inflammatory factors, reduces blood-brain barrier (BBB) damage and neuronal death, prevents vasospasms, and alleviates brain injury.

Epilepsy is a common neurological disorder characterized by recurrent, with HMGB1 overexpression in the hippocampus serving as a significant mediator in its development. Glycyrrhizin, an inhibitor of HMGB1, alleviates hippocampal neuronal damage and exerts neuroprotective effects by regulating several HMGB1-mediated signaling pathways, such as the HMGB1/P38 mitogen-activated protein kinase (P38MAPK) and HMGB1/toll-like receptor 4 (TLR4)/ phosphorylated nuclear factor kappa B (P-NF-κB) pathways. Moreover, glycyrrhizic acid activates sirtuin 3 (SIRT3) to reduce hippocampal pathological damage, inhibits the expression of inflammatory cytokines, and protects temporal lobe epilepsy (TLE) neurons by suppressing ferroptosis through the microRNA-194-5p/prostaglandin-endoperoxide synthase 2 (PTGS2) axis.

Traumatic brain injury (TBI) is typically caused by head trauma and can lead to severe complications. Glycyrrhizin improves neurological recovery after TBI by downregulating HMGB1 and its receptors, thereby reducing the brain injury volume. Glycyrrhizin also demonstrates therapeutic potential in pediatric TBI by improving spatial memory and motor learning deficits. Additionally, in spinal cord injury (SCI), glycyrrhizin can enhance neurological recovery by suppressing the inflammatory response, protecting the BBB, and modulating microglial cell polarization. Glycyrrhizin improves various neurological disorders by inhibiting the HMGB1/TLR4 signaling pathway, reducing pro-inflammatory cytokines, and decreasing hippocampal microglial activation. This helps alleviate anxiety, depression, and other behavioral issues while improving cognitive function. Glycyrrhizin also ameliorates obesity-related cognitive dysfunction by alleviating hippocampal inflammation and reducing cell apoptosis, and can inhibit NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation after TBI, thus improving cognitive function. Glycyrrhizin restores cognitive impairment in different age groups. It can improve memory in the elderly and reduce the impact of general anesthesia on cognitive function in children. In addition, it reduces inflammation in postoperative cognitive dysfunction (POCD) by inhibiting the expression of HMGB1 and alleviating the symptoms of Alzheimer’s disease (AD). Glycyrrhizin improves memory damage caused by tauopathies by modulating the p-tau, NF-κB, and p38-mitogen-activated protein kinase (MAPK) signaling pathways. It also restores mitochondrial function, regulates apoptosis, and exerts neuroprotective effects.

In neurodegenerative diseases, such as AD and Parkinson’s disease (PD), glycyrrhizin alleviates cognitive deficits by inhibiting microglial activation and acetylcholinesterase activity. It reduces neuronal death in PD by binding to HMGB1, exhibiting antioxidant and anti-inflammatory effects. It also improves Parkinson’s disease-related depression (PDD) by modulating glucocorticoid receptor pathways. In mood disorders, glycyrrhizin regulates the kynurenine pathway, reduces inflammatory factors, such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), and modulates the excitability of hippocampal neurons, improving depressive-like behaviors. Studies have also suggested that glycyrrhizin alleviates depressive symptoms caused by neuropathic pain and radiation by inhibiting the HMGB1/NLRP3 pathway. Additionally, glycyrrhizin demonstrated potential efficacy in treating schizophrenia, showing promise as a lysine acetyltransferase 2A (KAT2) inhibitor with therapeutic potential for mental disorders.

DN is a common complication of diabetes, affecting peripheral and autonomic nerves. Glycyrrhizin improves diabetic peripheral neuropathy (DPN) by blocking the HMGB1 signaling pathway, reducing the expression of TLR4, NLRP3, and C-X-C motif chemokine receptor 4 (CXCR4) and decreasing neuroinflammation. Glycyrrhizin also alleviates the inflammatory response of DPN and protects nerve function by inhibiting the HMGB1/receptor for advanced glycation end products (RAGE)/P38MAPK/NF-κB signaling pathway. The results of other studies suggest that glycyrrhizin can alleviate diabetes-induced neuropathic hyperalgesia and cell death and may serve as an adjunctive treatment for DPN. Furthermore, diabetes increases the risk of stroke, and glycyrrhizin has been shown to reduce post-stroke neural damage by blocking the excessive expression of HMGB1 and other inflammatory factors, making it a potential therapeutic candidate for diabetic stroke. The effect of diabetes on the retina is also significant, and glycyrrhizin exhibits a protective effect by inhibiting HMGB1, reducing optic nerve demyelination, and alleviating chronic ocular inflammation.

Glycyrrhizin exhibits neuroprotective effects against chemical neurotoxicity. For example, glycyrrhizin has been shown to protect nerves from damage induced by substances, such as aluminum and chlorpyrifos by inhibiting oxidative stress responses. Moreover, glycyrrhizin has been found to alleviate paclitaxel-induced neurotoxicity, offering a new therapeutic direction for the prevention of peripheral neuropathy. Based on in vivo and in vitro experimental evidence [Supplementary Tables 1 and 2, http://links.lww.com/CM9/C602], glycyrrhizin has been shown to play a crucial role in the treatment of various nervous system diseases. By inhibiting HMGB1 and its associated signaling pathways, glycyrrhizin significantly alleviates the neuroinflammatory response, reduces oxidative stress, improves mitochondrial function, and regulates biological processes, such as apoptosis, thus providing neuroprotective effects [Figure 1]. Although glycyrrhizin is widely added to food and has a good safety profile, it is not entirely free of potential toxicity or side effects. Potential side effects of glycyrrhizin include the possibility of inducing excess mineralocorticoid activity, inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the kidneys, and elevated cortisol levels in the adrenal cortex, which could pose health risks to patients. When administered intravenously, some patients may experience adverse reactions, such as seizures and hemolysis, which limit its clinical applications.^[3] Therefore, future research should focus on safety evaluations of the long-term use of glycyrrhizin, especially regarding its impact on patients undergoing long-term treatment for neurological disorders.

Figure 1.

The main mechanism of action by which glycyrrhizin exerts neurotherapeutic effects. Glycyrrhizin regulates multiple signaling pathways by inhibiting HMGB1, such as the HMGB1/TLRs/NF-κB pathway, which promotes the expression of cytokines like TNF-α, IL-1β, and IL-6. Glycyrrhizin also modulates the expression of the RAGE/P38MAPK and RAGE/GSK-3β/NRF2 pathways, and by activating the NRF2-related pathways, it inhibits ROS damage, alleviates oxidative stress and inflammation, and enhances cellular protection and repair mechanisms. ↓: Low expression; ↑: High expression; Bax: Bcl-2-associated X protein; BBB: Blood-brain barrier; Bcl-2: B-cell lymphoma 2; CASP3: Caspase-3; ERK1/2: Extracellular signal-regulated kinase 1/2; GPX4: Glutathione peroxidase 4; GSH: Glutathione; GSK-3β: Glycogen synthase kinase 3 beta; GSSG: Oxidized glutathione; HMGB1: High mobility group box 1; IL-1β: Interleukin 1 beta; IL-6: Interleukin 6; LC3: Microtubule-associated protein 1 light chain 3; MAPK: Mitogen-activated protein kinase; MDA: Malondialdehyde; MMP9: Matrix metallopeptidase 9; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NRF2: Nuclear factor erythroid 2-related factor 2; P38: P38 mitogen-activated protein kinase; P65: P65 subunit of NF-κB; PAGE: Receptor for advanced glycation end products; PTGS2: Prostaglandin-endoperoxide synthase 2; RAS: Rat sarcoma; ROS: Reactive oxygen species; SOD: Superoxide dismutase; TLRs: Toll-like receptors; TNF-α: Tumor necrosis factor alpha.

Glycyrrhizin’s maximal clinical efficacy are limited by poor bioavailability. Nanotechnology advancements in drug delivery systems, including nanoparticles, micelles, and dendritic macromolecules, are expected to improve its effectiveness.^[4] Combination therapy with glycyrrhizin may become a new direction for the future treatment of neurological diseases.^[5] Many neurological disorders involve multiple pathological mechanisms, making it difficult to improve the condition of the patient through treatment with a single drug. Therefore, the combination of glycyrrhizin with other medications or therapeutic approaches, such as antioxidants, anti-inflammatory drugs, and immunomodulatory drugs, may lead to stronger synergistic effects. This approach provides multi-target intervention, enhancing treatment comprehensiveness and effectiveness. Clinical studies have shown that glycyrrhizin, as an adjunct treatment for major depressive disorder, significantly improves depressive symptoms and treatment responses, accelerating clinical outcomes in depression patients.

In addition to pharmacological treatment, dietary interventions and lifestyle adjustments play important roles in the treatment of neurological diseases. For example, diets rich in antioxidants, low-sugar diets, supplementation with omega-3 fatty acids, and vitamin D have been shown to have positive effects on neuroprotection. Thus, the combined use of glycyrrhizin may complement healthy dietary interventions and offer a comprehensive therapeutic strategy.

In conclusion, glycyrrhizin, a promising neuroprotective agent, has shown positive effects in the treatment of certain neurological diseases; however, further clinical research and experimental validation are required. Future studies should focus on the long-term safety, optimal dosing regimen, potential of combination therapies, and the impact of dietary interventions and lifestyle changes on therapeutic effects. Through an in-depth exploration of these aspects, we aimed to better understand the mechanisms of action of glycyrrhizin and to provide more scientifically grounded and comprehensive strategies for the treatment of neurological diseases.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82003879), Project of Science and Technology Department of Sichuan Province (Nos. 2023NSFSC1928 and 2023NSFSC1992), Project of State Administration of Traditional Chinese Medicine of China (No. ZYYCXTD-D-202209), Project of Sichuan Provincial Administration of Traditional Chinese Medicine (Nos. 2022C001 and 2024ZD02), the Fundamental Research Funds for the central Universities, and Sichuan University Interdisciplinary Innovation Fund.

Conflicts of interest

None.

Supplementary Material

cm9-139-457-s001.pdf ^{(346.2KB, pdf)}