2026 ECNP Congress

EP01-1086

Glycyrrhizin improves neuroinflammation and cognitive impairment in Alzheimer’s disease model mice

Guifeng Wang — K. Hiramoto, N. Ma, S. Ohnishi, N. Yoshikawa, M. Murata, S. Kawanishi · Suzuka University of Medical Science, Acupuncture and Moxibustion Medical Science, Suzuka, Japan

2026 ECNP Congress

Background

Neuroinflammation is a central driver of Alzheimer’s disease (AD) pathology, contributing to synaptic dysfunction, amyloid-β accumulation, and tau hyperphosphorylation [1]. High mobility group box 1 (HMGB1) is a key mediator of this process, acting as a stress-associated signal that promotes inflammatory responses and microglial activation in the central nervous system [2-3]. In addition, the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway contributes to neuroinflammatory signalling in response to cellular stress and damage, thereby amplifying inflammatory cascades [4], in which HMGB1 is released extracellularly and activates NF-κB pathway. Glycyrrhizin, a bioactive compound of licorice, exerts anti-inflammatory effects primarily through inhibition of HMGB1 [5].

Objectives

In this study, we investigated the role of HMGB1 in AD-related neuroinflammation and the effects of glycyrrhizin and its stereoisomer on cognitive function, neuroinflammatory responses, and pathological changes in an AD mouse model, senescence-accelerated mouse prone 8 (SAMP8) mice.

Methods

We used four-month-old SAMP8 mice and senescence-accelerated mouse resistant 1 (SAMR1), as control, and glycyrrhizin (15 mg/kg, mainly 18β form) and its stereoisomer (18α form) were administered orally three times per week for three months. Cognitive function was assessed using a passive avoidance test to evaluate learning and memory performance. Plasma levels of α-Klotho, insulin-like growth factor-1 (IGF-1), 2′3′-cyclic GMP–AMP, HMGB1, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by ELISA. Hippocampal microglial activation, amyloid-β deposition, and phosphorylated tau were evaluated by immunohistochemistry. Statistical analyses were performed using one-way analysis of variance followed by Tukey’s multiple comparison test among three groups, and unpaired and paired Student’s t tests between two groups. A p value < 0.05 was considered statistically significant.

Results

SAMP8 mice exhibited impaired memory performance compared with controls, with no significant increase in latency between acquisition and retention trials, whereas glycyrrhizin treatment significantly improved retention latency. Plasma α-Klotho and IGF-1 levels were significantly reduced in SAMP8 mice, and were restored following glycyrrhizin administration. HMGB1, 2′3′-cyclic GMP–AMP, IL-6, and TNF-α levels were significantly elevated in SAMP8 mice, and were reduced after the treatment. Glycyrrhizin also significantly decreased hippocampal microglial activation, amyloid-β deposition, and phosphorylated tau accumulation. The 18α isomer appeared to be greater efficacy than the 18β isomer across multiple parameters, including inflammatory cytokine reduction and behavioral improvement, suggesting stereoisomer-specific differences and potential functional relevance.

Conclusions

Glycyrrhizin attenuates neuroinflammatory responses and ameliorates cognitive impairment in an AD mouse model, potentially through inhibition of HMGB1 and associated inflammatory cascades, with additional modulation of stress-related signalling pathways including cGAS–STING. These findings support the validity of targeting neuroinflammation in Alzheimer’s disease, and it suggests that glycyrrhizin could be a potential therapeutic agent for neurodegenerative diseases.Taken together, these results also provide insight into HMGB1-associated inflammatory mechanisms relevant to AD progression and suggest the importance of modulating inflammation-related pathways in neurodegenerative disorders.

References

  1. Mary A, Mancuso R, Heneka MT., 2024. Immune Activation in Alzheimer Disease. Annu Rev Immunol,42(1):585-613.
  2. Paudel YN, Angelopoulou E, Piperi C, Othman I, Aamir K, Shaikh MF.,2020. Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting. Cells,9(2).
  3. Ikram FZ, Arulsamy A, Retinasamy T, Shaikh MF.,2022. The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review. Curr Neuropharmacol,20(11):2221-45.
  4. Zhang Y, Zou M, Wu H, Zhu J, Jin T., 2024. The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases. Neurobiol Dis,202:106710.
  5. Amrutha S, Prasad TSK, Modi PK., 2026. Glycyrrhizic Acid Attenuates Abeta(42)-Induced Neurodegeneration Through Coordinated Regulation of Oxidative Stress, Synaptic Markers, and Key Alzheimer’s Signaling Pathways. Cells,15(5).