REGULATORY EFFECT OF MYRICETIN ON DEPRESSIVE-LIKE BEHAVIORS IN MICE WITH CHRONIC UNPREDICTABLE MILD STRESS

GE Ling-ling; WANG Yu-ting; XIA Shu-fang

Acta Nutrimenta Sinica ›› 2026, Vol. 48 ›› Issue (2) : 170-179.

GE Ling-ling¹, WANG Yu-ting², XIA Shu-fang²

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Abstract

Objective To study the effect of myricetin and its underlying mechanism on depressive-like behaviors in mice with chronic unpredictable mild stress. Methods Fifty-six male C57BL/6J mice were randomly divided into four groups: control group (Con), CUMS model group (CUMS), myricetin intervention group (Myr, 100 mg/(kg∙bw) myricetin), and fluoxetine intervention group (FLX). The mice received oral gavage of myricetin and fluoxetine prior to daily stress. Eight weeks later, open-field, tail suspension, elevated plus maze, and sucrose preference tests were used to assess the depressive-like behaviors. The hippocampal histopathological morphology, microRNA (miRNA) expressions, and the neurotransmitters and inflammatory cytokines were measured. Additionally, the relative expression of miRNA targeting Nlrp3, as well as genes and proteins associated with the NLRP3 inflammatory signaling pathway were determined. Results Myricetin significantly improved depressive-like behaviors in CUMS mice, manifested as significantly increased time spent and distance traveled in the central area of the open-field test, reduced immobility time, increased time spent and entries into the open arms, and elevated sucrose preference index (P<0.05). Concurrently, the Myr group exhibited more orderly neuronal arrangement in hippocampal CA1, CA3, and DG regions, along with significantly elevated 5-hydroxytryptamine and dopamine levels. Compared with the Con group, CUMS induced significant alterations in 17 miRNAs expression, while myricetin significantly regulated the expression of 15 miRNAs compared to the CUMS group. Myricetin significantly upregulated the down-regulated expression of miR-223 and miR-30a induced by CUMS to inhibit the expression of NLRP3 and its downstream Cleaved caspase-1 (p20), and reduced interleukin-1β (IL-1β), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α) levels (P<0.05). Conclusion Myricetin inhibit the activation of the hippocampal NLRP3/Caspase-1 signaling pathway and suppress inflammation, by regulating the expression of NLRP3-targeted miR-223 and miR-30a and thereby improves depressive-like behaviors in mice.

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depression / myricetin / microRNA / NLRP3 / mouse

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GE Ling-ling, WANG Yu-ting, XIA Shu-fang. REGULATORY EFFECT OF MYRICETIN ON DEPRESSIVE-LIKE BEHAVIORS IN MICE WITH CHRONIC UNPREDICTABLE MILD STRESS[J]. Acta Nutrimenta Sinica. 2026, 48(2): 170-179

References

[1] Herrman H, Patel V, Kieling C, et al. Time for united action on depression: a Lancet-World Psychiatric Association Commission[J]. Lancet, 2022, 399: 957–1022.
[2] Lu J, Xu XF, Huang YQ, et al. Prevalence of depressive disorders and treatment in China: a cross-sectional epidemiological study[J]. Lancet Psychiatry, 2021, 8: 981–990.
[3] Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis[J]. Lancet, 2018, 391: 1357–1366.
[4] Beurel E, Toups M,Nemeroff CB.The bidirectional relationship of depression and inflammation: double trouble[J]. Neuron, 2020, 107: 234–256.
[5] Milaneschi Y, Kappelmann N, Ye Z, et al. Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts[J]. Mol Psychiatry, 2021, 26: 7393–7402.
[6] Hao R, Gao X, Lu Q, et al. CUMS induces depressive-like behaviors and cognition impairment by activating the ERS-NLRP3 signaling pathway in mice[J]. J Affect Disord, 2025, 369: 547–558.
[7] Bhatt S, Devadoss T, Jha NK, et al. Targeting inflammation: a potential approach for the treatment of depression[J]. Metab Brain Dis, 2023, 38: 45–59.
[8] Agraharam G, Girigoswami A, Girigoswami K.Myricetin: a multifunctional flavonol in biomedicine[J]. Curr Pharmacol Rep, 2022, 8: 48–61.
[9] Liu P, Zhou Y, Shi J, et al. Myricetin improves pathological changes in 3×Tg-AD mice by regulating the mitochondria-NLRP3 inflammasome-microglia channel by targeting P38 MAPK signaling pathway[J]. Phytomedicine, 2023, 115: 154801.
[10] Pereira M, Siba IP, Acco A, et al. Myricitrin exhibits antidepressant-like effects and reduces IL-6 hippocampal levels in the chronic mild stress model[J]. Behav Brain Res, 2022, 429: 113905.
[11] Ding R, Su D, Zhao Q, et al. The role of microRNAs in depression[J]. Front Pharmacol, 2023, 14: 1129186.
[12] Wang W, Yang T, Liu N, et al. MiR-223-3p inhibits hippocampal neurons injury and exerts anti- anxiety/depression-like behaviors by directly targeting NLRP3[J]. Psychopharmacology, 2025, 242: 1797–1809.
[13] Ma Z, Wang G, Cui L, et al. Myricetin attenuates depressant-like behavior in mice subjected to repeated restraint stress[J]. Int J Mol Sci, 2015, 16: 28377–28385.
[14] Sun L, Zhang H, Cao Y, et al. Fluoxetine ameliorates dysbiosis in a depression model induced by chronic unpredicted mild stress in mice[J]. Int J Med Sci, 2019, 16: 1260–1270.
[15] Liu X, Hao J, Yao E, et al. Polyunsaturated fatty acid supplement alleviates depression-incident cognitive dysfunction by protecting the cerebrovascular and glymphatic systems[J]. Brain Behav Immun, 2020, 89: 357–370.
[16] Nollet M.Models of depression: unpredictable chronic mild stress in mice[J]. Curr Protoc, 2021, 1: e208.
[17] Becker M, Pinhasov A, Ornoy A.Animal models of depression: what can they teach us about the human disease?[J]. Diagnostics, 2021, 11: 123.
[18] Sharma S, Chawla S, Kumar P, et al. The chronic unpredictable mild stress (CUMS) paradigm: bridging the gap in depression research from bench to bedside[J]. Brain Res, 2024, 1843: 149123.
[19] Robinson E, Bangasser DA.Innovating translational models of affective disorders[J]. Psychopharmacology, 2023, 240: 2217–2220.
[20] Larosa A, Wong TP.The hippocampus in stress susceptibility and resilience: reviewing molecular and functional markers[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2022, 119: 110601.
[21] Bremshey S, Groß J, Renken K, et al. The role of serotonin in depression—a historical roundup and future directions[J]. J Neurochem, 2024, 168: 1751–1779.
[22] Dunlop BW, Nemeroff CB.The role of dopamine in the pathophysiology of depression[J]. Arch Gen Psychiatry, 2007, 64: 327–337.
[23] Fan N, Luo Y, Ou Y, et al. Altered serum levels of TNF-α, IL-6, and IL-18 in depressive disorder patients[J]. Hum Psychopharmacol Clin Exp, 2017, 32: e2588.
[24] Krügel U, Fischer J, Radicke S, et al. Antidepressant effects of TNF-α blockade in an animal model of depression[J]. J Psychiatr Res, 2013, 47: 611–616.
[25] Al-Hakeim HK, Twayej AJ, Al- Dujaili AH.Reduction in serum IL-1β, IL-6, and IL-18 levels and beck depression inventory-II score by combined sertraline and ketoprofen administration in major depressive disorder: a clinical trial[J]. Neurol Psychiat Brain Res,2018, 30: 148–153.
[26] Jang JH, Lee SH, Jung K, et al. Inhibitory effects of myricetin on lipopolysaccharide-induced neuroinflam-mation[J]. Brain Sci, 2020, 10: 32.
[27] Wang C, Ouyang S, Zhu X, et al. Myricetin suppresses traumatic brain injury-induced inflammatory response via EGFR/AKT/STAT pathway[J]. Sci Rep, 2023, 13: 22764.
[28] Ghaffaripour Jahromi G, Razi S, Rezaei N.NLRP3 inflammatory pathway. Can we unlock depression?[J]. Brain Res, 2024, 1822: 148644.
[29] Alcocer-Gómez E, De Miguel M, Casas-Barquero N, et al. NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder[J]. Brain Behav Immun, 2014, 36: 111–117.
[30] Pan Y, Chen XY, Zhang QY, et al. Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats[J]. Brain Behav Immun, 2014, 41: 90–100.
[31] Alcocer-Gómez E, Ulecia-Morón C, Marín-Aguilar F, et al. Stress-induced depressive behaviors require a functional NLRP3 inflammasome[J]. Mol Neurobiol, 2016, 53: 4874–4882.
[32] Li W, Niu L, Liu Z, et al. Inhibition of the NLRP3 inflammasome with MCC950 prevents chronic social isolation-induced depression-like behavior in male mice[J]. Neurosci Lett, 2021, 765: 136290.
[33] Chen H, Lin H, Xie S, et al. Myricetin inhibits NLRP3 inflammasome activation via reduction of ROS-dependent ubiquitination of ASC and promotion of ROS-independent NLRP3 ubiquitination[J]. Toxicol Appl Pharmacol, 2019, 365: 19–29.
[34] 张晓艳,夏淑芳,陈肖.杨梅酮对衰老小鼠认知障碍的延缓作用及机制研究[J].营养学报, 2024, 46: 365-371.
[35] Gorinski N, Bijata M, Prasad S, et al. Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors[J]. Nat Commun, 2019, 10: 3924.
[36] Xu W, Wang Y, Ma Y, et al. MiR-223 plays a protecting role in neutrophilic asthmatic mice through the inhibition of NLRP3 inflammasome[J]. Respir Res, 2020, 21: 116.
[37] Yang Q, Zhao W, Chen Y, et al. RelA/MicroRNA-30a/NLRP3 signal axis is involved in rheumatoid arthritis via regulating NLRP3 inflammasome in macrophages[J]. Cell Death Dis, 2021, 12: 1060.
[38] Wu H, Liu J, Zhang Y, et al. miR-22 suppresses cell viability and EMT of ovarian cancer cells via NLRP3 and inhibits PI3K/AKT signaling pathway[J]. Clin Transl Oncol, 2021, 23: 257–264.
[39] Ying Y, Mao Y, Yao M.NLRP3 Inflammasome activation by microrna-495 promoter methylation may contribute to the progression of acute lung injury[J]. Mol Ther Nucleic Acids, 2019, 18: 801–814.
[40] Li D, Yang H, Ma J, et al. MicroRNA-30e regulates neuroinflammation in MPTP model of Parkinson’s disease by targeting Nlrp3[J]. Hum Cell, 2018, 31: 106–115.
[41] Yu J, Chen J, Yang H, et al. Overexpression of miR-200a-3p promoted inflammation in sepsis-induced brain injury through ROS-induced NLRP3[J]. Int J Mol Med, 2019, 44: 1811–1823.
[42] Wang X, Chi J, Dong B, et al. MiR-223-3p and miR-22-3p inhibit monosodium urate-induced gouty inflammationby targeting NLRP3[J]. Int J Rheum Dis, 2021, 24(4): 599–607.
[43] Zhang M, Lan H, Peng S, et al. MiR-223-3p attenuates radiation-induced inflammatory response and inhibits the activation of NLRP3 inflammasome in macrophages[J]. Int Immunopharmacol, 2023. 122: 110616.
[44] Ambati M, Apicella I, Wang SB, et al. Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration[J]. Proc Natl Acad Sci, 2021, 118: e2102975118.