Abstract
Emerging evidence indicates that NLRP3 inflammasome-induced inflammation plays a crucial role in the pathogenesis of depression. Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of depression. Metformin has been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. We used a chronic mild stress model of depression and cultured primary macrophage to investigate the effects of metformin on depression and its underlying mechanisms. We demonstrated that metformin alleviated depressive-like behaviors in the chronic mild stress-induced anhedonia model of depression. We further found that metformin significantly suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1β secretion in both peripheral macrophages and central hippocampus. Our findings reveal that metformin confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation. In light of metformin favorable properties, it should be evaluated in the treatment of depression and related neurologic disorders characterized by NLRP3 inflammasome activation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdallah MS, Mosalam EM, Zidan AA, Elattar KS, Zaki SA, Ramadan AN, Ebeid AM (2020) The antidiabetic metformin as an adjunct to antidepressants in patients with major depressive disorder: a proof-of-concept, randomized, double-blind, placebo-controlled trial. Neurotherapeutics. https://doi.org/10.1007/s13311-020-00878-7
Ahmadi S, Razazan A, Nagpal R, Jain S, Wang B, Mishra SP, Wang S, Justice J, Ding J, McClain DA, Kritchevsky SB, Kitzman D, Yadav H (2020) Metformin reduces aging-related leaky gut and improves cognitive function by beneficially modulating gut microbiome/goblet cell/mucin axis. J Gerontol A Biol Sci Med Sci 75:e9–e21
Alcocer-Gomez E, Cordero MD (2014) NLRP3 inflammasome: a new target in major depressive disorder. CNS Neurosci Ther 20:294–295
Alcocer-Gomez E, de Miguel M, Casas-Barquero N, Nunez-Vasco J, Sanchez-Alcazar JA, Fernandez-Rodriguez A, Cordero MD (2014) NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav Immun 36:111–117
Alcocer-Gomez E, Ulecia-Moron C, Marin-Aguilar F, Rybkina T, Casas-Barquero N, Ruiz-Cabello J, Ryffel B, Apetoh L, Ghiringhelli F, Bullon P, Sanchez-Alcazar JA, Carrion AM, Cordero MD (2016) Stress-induced depressive behaviors require a functional NLRP3 inflammasome. Mol Neurobiol 53:4874–4882
Alcocer-Gomez E, Casas-Barquero N, Williams MR, Romero-Guillena SL, Canadas-Lozano D, Bullon P, Sanchez-Alcazar JA, Navarro-Pando JM, Cordero MD (2017) Antidepressants induce autophagy dependent-NLRP3-inflammasome inhibition in major depressive disorder. Pharmacol Res 121:114–121
Chen L, Na R, Boldt E, Ran Q (2015) NLRP3 inflammasome activation by mitochondrial reactive oxygen species plays a key role in long-term cognitive impairment induced by paraquat exposure. Neurobiol Aging 36:2533–2543
Choi AJ, Ryter SW (2014) Inflammasomes: molecular regulation and implications for metabolic and cognitive diseases. Mol Cells 37:441–448
Du RH, Tan J, Sun XY, Lu M, Ding JH, Hu G (2016) Fluoxetine inhibits NLRP3 inflammasome activation: implication in depression. Int J Neuropsychopharmacol 19(9):pyw037
Eitel J, Meixenberger K, van Laak C, Orlovski C, Hocke A, Schmeck B, Hippenstiel S, N’Guessan PD, Suttorp N, Opitz B (2012) Rac1 regulates the NLRP3 inflammasome which mediates IL-1beta production in Chlamydophila pneumoniae infected human mononuclear cells. PLoS ONE 7:e30379
Fang W, Zhang J, Hong L, Huang W, Dai X, Ye Q, Chen X (2020) Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation. J Affect Disord 260:302–313
Fusco R, Siracusa R, Genovese T, Cuzzocrea S, Di Paola R (2020) Focus on the role of NLRP3 inflammasome in diseases. Int J Mol Sci 21(12):4223
Inserra A, Mastronardi CA, Rogers G, Licinio J, Wong ML (2019) Neuroimmunomodulation in major depressive disorder: focus on caspase 1, inducible nitric oxide synthase, and interferon-gamma. Mol Neurobiol 56:4288–4305
Jeon SA, Lee E, Hwang I, Han B, Park S, Son S, Yang J, Hong S, Kim CH, Son J, Yu JW (2017) NLRP3 inflammasome contributes to lipopolysaccharide-induced depressive-like behaviors via Indoleamine 2,3-dioxygenase induction. Int J Neuropsychopharmacol 20:896–906
Kaufmann FN, Costa AP, Ghisleni G, Diaz AP, Rodrigues ALS, Peluffo H, Kaster MP (2017) NLRP3 inflammasome-driven pathways in depression: clinical and preclinical findings. Brain Behav Immun 64:367–383
Khedr SA, Elmelgy AA, El-Kharashi OA, Abd-Alkhalek HA, Louka ML, Sallam HA, Aboul-Fotouh S (2018) Metformin potentiates cognitive and antidepressant effects of fluoxetine in rats exposed to chronic restraint stress and high fat diet: potential involvement of hippocampal c-Jun repression. Naunyn Schmiedebergs Arch Pharmacol 391:407–422
Lempriere S (2020) NLRP3 inflammasome activity as biomarker for primary progressive multiple sclerosis. Nat Rev Neurol 16:350
Li R, Wang X, Qin T, Qu R, Ma S (2016) Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1beta production and NLRP3 inflammasome activation in the rat brain. Behav Brain Res 296:318–325
Nazarian-Samani Z, Sewell RDE, Rafieian-Kopaei M (2020) Inflammasome signaling and other factors implicated in atherosclerosis development and progression. Curr Pharm Des 26:2583–2590
Pan Y, Chen XY, Zhang QY, Kong LD (2014) Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats. Brain Behav Immun 41:90–100
Park E, Na HS, Song YR, Shin SY, Kim YM, Chung J (2014) Activation of NLRP3 and AIM2 inflammasomes by Porphyromonas gingivalis infection. Infect Immun 82:112–123
Ren GF, Xiao LL, Ma XJ, Yan YS, Jiao PF (2020) Metformin decreases insulin resistance in type 1 diabetes through regulating p53 and RAP2A in vitro and in vivo. Drug Des Dev Ther 14:2381–2392
Severini C, Barbato C, Di Certo MG, Gabanella F, Petrella C, Di Stadio A, de Vincentiis M, Polimeni A, Ralli M, Greco A (2020) Alzheimer’s disease: new concepts on the role of autoimmunity and of NLRP3 inflammasome in the pathogenesis of the disease. Curr Neuropharmacol. https://doi.org/10.2174/1570159X18666200621204546
Song MT, Ruan J, Zhang RY, Deng J, Ma ZQ, Ma SP (2018) Astragaloside IV ameliorates neuroinflammation-induced depressive-like behaviors in mice via the PPARgamma/NF-kappaB/NLRP3 inflammasome axis. Acta Pharmacol Sin 39:1559–1570
Taene A, Khalili-Tanha G, Esmaeili A, Mobasheri L, Kooshkaki O, Jafari S, Shokouhifar A, Sarab GA (2020) The association of major depressive disorder with activation of NLRP3 inflammasome, lipid peroxidation, and total antioxidant capacity. J Mol Neurosci 70:65–70
Tseng CH (2020) Metformin use is associated with a lower risk of inflammatory bowel disease in patients with type 2 diabetes mellitus. J Crohns Colitis. https://doi.org/10.1093/ecco-jcc/jjaa136
Wittenberg GM, Greene J, Vertes PE, Drevets WC, Bullmore ET (2020) Major depressive disorder is associated with differential expression of innate immune and neutrophil-related gene networks in peripheral blood: a quantitative review of whole-genome transcriptional data from case-control studies. Biol Psychiatry S0006–3223(20):31591–2
Wu X, Liu Y, Tu D, Liu X, Niu S, Suo Y, Liu T, Li G, Liu C (2020) Role of NLRP3-inflammasome/caspase-1/galectin-3 pathway on atrial remodeling in diabetic rabbits. J Cardiovasc Transl Res. https://doi.org/10.1007/s12265-020-09965-8
Zemdegs J, Martin H, Pintana H, Bullich S, Manta S, Marques MA, Moro C, Laye S, Ducrocq F, Chattipakorn N, Chattipakorn SC, Rampon C, Penicaud L, Fioramonti X, Guiard BP (2019) Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J Neurosci 39:5935–5948
Zhang Y, Liu L, Liu YZ, Shen XL, Wu TY, Zhang T, Wang W, Wang YX, Jiang CL (2015) NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation. Int J Neuropsychopharmacol 18(8):pyv006
Zhong Z, Sanchez-Lopez E, Karin M (2016) Autophagy, NLRP3 inflammasome and auto-inflammatory/immune diseases. Clin Exp Rheumatol 34:12–16
Funding
This work was supported by the grant from the Key Program of Basic Research of Chaoyang Hospital.
Author information
Authors and Affiliations
Contributions
RWD designed the study, performed the experiments, analyzed the data, and wrote the paper. WGB conceived the study and revised the paper. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval and consent to participate
The animals used in our study were treated in accordance with protocols approved by the Institutional Animal Care and Use Committee of Chaoyang Hospital.
Consent for publication
Not applicable.
Availability of data and materials
All data generated and/or analyzed during this study are included in this article.
Code availability
Not applicable.
Additional information
Communicated by Sreedharan Sajikumar.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Du, RW., Bu, WG. Metformin improves depressive-like symptoms in mice via inhibition of peripheral and central NF-κB-NLRP3 inflammation activation. Exp Brain Res 238, 2549–2556 (2020). https://doi.org/10.1007/s00221-020-05911-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-020-05911-x