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Tetramethylpyrazine ameliorates depression by inhibiting TLR4-NLRP3 inflammasome signal pathway in mice

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Abstract

Depression is a common but serious mental illness; meanwhile, it is also an inflammatory disorder. Toll-like receptor 4 (TLR4), as the pattern recognition receptor, has been shown to play a vital role in neuroinflammation. The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome acts as an important signaling molecule downstream of TLR4 and can promote the maturation of inflammatory cytokines, such as interleukin-1β (IL-1β). Tetramethylpyrazine (TMP) is a natural compound with neuroprotective effects but with unknown mechanisms on its antidepressant-like effect. In this study, we hypothesized that TMP ameliorates depression may be through the inhibition of the TLR4-NF-κB-NLRP3 signal pathway. Our results have shown that chronic unpredictable mild stress (CUMS) that induced the decreased sucrose preference and increased immobile time was prominently reversed by TMP and fluoxetine. Additionally, we also found that CUMS induced the upregulation of proinflammatory cytokines; TLR4 and NLRP3-associated proteins were significantly suppressed by TMP in the prefrontal cortex and hippocampus. TMP also exhibited potent antioxidant effects and increased the monoamine levels in the serum and brain, such as increasing the activity of SOD and GSH-Px, and reducing the activity of MDA in the serum, and elevating the 5-HT and NE concentration in the serum and brain. Moreover, treatment with Cli-095 (TLR4 inhibitor) also markedly inhibited CUMS-induced depression-like behaviors. Taken together, our findings suggested that TMP exerted a potential antidepressant-like effect in CUMS mice, and the molecular mechanisms may relate to inhibit the TLR4-NF-κB-NLRP3 signaling pathway in the brain.

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References

  • Abd El-Fattah AA, Fahim AT, Sadik NAH, Ali BM (2018) Resveratrol and dimethyl fumarate ameliorate depression-like behaviour in a rat model of chronic unpredictable mild stress. Brain Res 1701:227–236

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Alvarez K, Vasquez G (2017) Damage-associated molecular patterns and their role as initiators of inflammatory and auto-immune signals in systemic lupus erythematosus. Int Rev Immunol 36:259–270

    Article  CAS  PubMed  Google Scholar 

  • Amiresmaeili A, Roohollahi S, Mostafavi A, Askari N (2018) Effects of oregano essential oil on brain TLR4 and TLR2 gene expression and depressive-like behavior in a rat model. Res Pharm Sci 13:130–141

    Article  PubMed  PubMed Central  Google Scholar 

  • Belmaker RH, Agam G (2008) Major depressive disorder. N Engl J Med 358:55–68

    Article  CAS  PubMed  Google Scholar 

  • Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–151

    Article  CAS  PubMed  Google Scholar 

  • Carta S, Castellani P, Delfino L, Tassi S, Vene R, Rubartelli A (2009) DAMPs and inflammatory processes: the role of redox in the different outcomes. J Leukoc Biol 86:549–555

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Chen W, Zhu J, Chen N, Lu Y (2016) Potent anti-inflammatory activity of tetramethylpyrazine is mediated through suppression of NF-k. Iran J Pharm Res 15:197–204

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng Y, Pardo M, Armini RS, Martinez A, Mouhsine H, Zagury JF, Jope RS, Beurel E (2016) Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior. Brain Behav Immun 53:207–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng J, Dong S, Yi L, Geng D, Liu Q (2018) Magnolol abrogates chronic mild stress-induced depressive-like behaviors by inhibiting neuroinflammation and oxidative stress in the prefrontal cortex of mice. Int Immunopharmacol 59:61–67

    Article  CAS  PubMed  Google Scholar 

  • Deng XY, Li HY, Chen JJ, Li RP, Qu R, Fu Q, Ma SP (2015) Thymol produces an antidepressant-like effect in a chronic unpredictable mild stress model of depression in mice. Behav Brain Res 291:12–19

    Article  CAS  PubMed  Google Scholar 

  • Edberg D, Hoppensteadt D, Walborn A, Fareed J, Sinacore J, Halaris A (2018) Plasma C-reactive protein levels in bipolar depression during cyclooxygenase-2 inhibitor combination treatment. J Psychiatr Res 102:1–7

    Article  PubMed  Google Scholar 

  • Fang H, Wu Y, Huang X, Wang W, Ang B, Cao X, Wan T (2011) Toll-like receptor 4 (TLR4) is essential for Hsp70-like protein 1 (HSP70L1) to activate dendritic cells and induce Th1 response. J Biol Chem 286:30393–30400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fleshner M, Frank M, Maier SF (2017) Danger signals and inflammasomes: stress-evoked sterile inflammation in mood disorders. Neuropsychopharmacology 42:36–45

    Article  CAS  PubMed  Google Scholar 

  • Franklin TC, Xu C, Duman RS (2017) Depression and sterile inflammation: essential role of danger associated molecular patterns. Brain Behav Immun 72:2–13

  • Gao H, Zhu X, Xi Y, Li Q, Shen Z, Yang Y (2018) Anti-depressant-like effect of atractylenolide I in a mouse model of depression induced by chronic unpredictable mild stress. Exp Ther Med 15:1574–1579

    CAS  PubMed  Google Scholar 

  • Haneklaus M, O'Neill LA, Coll RC (2013) Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments. Curr Opin Immunol 25:40–45

    Article  CAS  PubMed  Google Scholar 

  • Iwata M, Ota KT, Li XY, Sakaue F, Li N, Dutheil S, Banasr M, Duric V, Yamanashi T, Kaneko K, Rasmussen K, Glasebrook A, Koester A, Song D, Jones KA, Zorn S, Smagin G, Duman RS (2016) Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biol Psychiatry 80:12–22

    Article  CAS  PubMed  Google Scholar 

  • Jeenger J, Sharma M, Mathur DM, Amandeep (2017) Associations of number and severity of depressive episodes with C-reactive protein and interleukin-6. Asian J Psychiatr 27:71–75

    Article  PubMed  Google Scholar 

  • Jiang B, Huang C, Chen XF, Tong LJ, Zhang W (2015) Tetramethylpyrazine produces antidepressant-like effects in mice through promotion of BDNF signaling pathway. Int J Neuropsychopharmacol 18

  • Jo EK, Kim JK, Shin DM, Sasakawa C (2016) Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol 13:148–159

    Article  CAS  PubMed  Google Scholar 

  • Kao TK, Ou YC, Kuo JS, Chen WY, Liao SL, Wu CW, Chen CJ, Ling NN, Zhang YH, Peng WH (2006) Neuroprotection by tetramethylpyrazine against ischemic brain injury in rats. Neurochem Int 48:166–176

    Article  CAS  PubMed  Google Scholar 

  • Karson A, Demirtas T, Bayramgurler D, Balci F, Utkan T (2013) Chronic administration of infliximab (TNF-alpha inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress. Basic Clin Pharmacol Toxicol 112:335–340

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Kessler RC (2012) The costs of depression. Psychiatr Clin North Am 35:1–14

    Article  PubMed  Google Scholar 

  • Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:593–602

    Article  PubMed  Google Scholar 

  • Koo JW, Russo SJ, Ferguson D, Nestler EJ, Duman RS (2010) Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci U S A 107:2669–2674

    Article  PubMed  PubMed Central  Google Scholar 

  • Kreisel T, Frank MG, Licht T, Reshef R, Ben-Menachem-Zidon O, Baratta MV, Maier SF, Yirmiya R (2014) Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry 19:699–709

    Article  CAS  PubMed  Google Scholar 

  • Li M, Shao H, Zhang X, Qin B (2016) Hesperidin alleviates lipopolysaccharide-induced Neuroinflammation in mice by promoting the miRNA-132 pathway. Inflammation 39:1681–1689

    Article  CAS  PubMed  Google Scholar 

  • Li H, Lin S, Qin T, Li H, Ma Z, Ma S (2017) Senegenin exerts anti-depression effect in mice induced by chronic un-predictable mild stress via inhibition of NF-kappaB regulating NLRP3 signal pathway. Int Immunopharmacol 53:24–32

    Article  CAS  PubMed  Google Scholar 

  • Li X, Wu T, Yu Z, Li T, Zhang J, Zhang Z, Cai M, Zhang W, Xiang J, Cai D (2018) Apocynum venetum leaf extract reverses depressive-like behaviors in chronically stressed rats by inhibiting oxidative stress and apoptosis. Biomed Pharmacother 100:394–406

    Article  CAS  PubMed  Google Scholar 

  • Liu D, Wang Z, Liu S, Wang F, Zhao S, Hao A (2011) Anti-inflammatory effects of fluoxetine in lipopolysaccharide (LPS)-stimulated microglial cells. Neuropharmacology 61:592–599

    Article  CAS  PubMed  Google Scholar 

  • Liu YM, Shen JD, Xu LP, Li HB, Li YC, Yi LT (2017) Ferulic acid inhibits neuro-inflammation in mice exposed to chronic unpredictable mild stress. Int Immunopharmacol 45:128–134

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Li X, Jiang S, Ge Q (2018) Tetramethylpyrazine protects against high glucose-induced vascular smooth muscle cell injury through inhibiting the phosphorylation of JNK, p38MAPK, and ERK. J Int Med Res 46:3318–3326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu XY, Kim CS, Frazer A, Zhang W (2006) Leptin: a potential novel antidepressant. Proc Natl Acad Sci U S A 103:1593–1598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu J, Shao RH, Jin SY, Hu L, Tu Y, Guo JY (2017) Acupuncture ameliorates inflammatory response in a chronic unpredictable stress rat model of depression. Brain Res Bull 128:106–112

    Article  CAS  PubMed  Google Scholar 

  • Luo DD, An SC, Zhang X (2008) Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress. Brain Res Bull 77:8–12

    Article  CAS  PubMed  Google Scholar 

  • Ma M, Ren Q, Yang C, Zhang JC, Yao W, Dong C, Ohgi Y, Futamura T, Hashimoto K (2017) Antidepressant effects of combination of brexpiprazole and fluoxetine on depression-like behavior and dendritic changes in mice after inflammation. Psychopharmacology 234:525–533

    Article  CAS  PubMed  Google Scholar 

  • Meyers CA, Albitar M, Estey E (2005) Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 104:788–793

    Article  CAS  PubMed  Google Scholar 

  • Motivala SJ, Sarfatti A, Olmos L, Irwin MR (2005) Inflammatory markers and sleep disturbance in major depression. Psychosom Med 67:187–194

    Article  CAS  PubMed  Google Scholar 

  • Pace TW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH, Heim CM (2006) Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry 163:1630–1633

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Pesarico AP, Sartori G, Bruning CA, Mantovani AC, Duarte T, Zeni G, Nogueira CW (2016) A novel isoquinoline compound abolishes chronic unpredictable mild stress-induced depressive-like behavior in mice. Behav Brain Res 307:73–83

    Article  CAS  PubMed  Google Scholar 

  • Porcu M, Urbano MR, Verri WA Jr, Barbosa DS, Baracat M, Vargas HO, Machado R, Pescim RR, Nunes SOV (2018) Effects of adjunctive N-acetylcysteine on depressive symptoms: modulation by baseline high-sensitivity C-reactive protein. Psychiatry Res 263:268–274

    Article  CAS  PubMed  Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336

    CAS  PubMed  Google Scholar 

  • Rizavi HS, Ren X, Zhang H, Bhaumik R, Pandey GN (2016) Abnormal gene expression of proinflammatory cytokines and their membrane-bound receptors in the lymphocytes of depressed patients. Psychiatry Res 240:314–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832

    Article  CAS  PubMed  Google Scholar 

  • Shao Z, Wu P, Wang X, Jin M, Liu S, Ma X, Shi H (2018) Tetramethylpyrazine protects against early brain injury and inhibits the PERK/Akt pathway in a rat model of subarachnoid hemorrhage. Neurochem Res 43:1650–1659

    Article  CAS  PubMed  Google Scholar 

  • Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT (2014) Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci 8:315

    Article  PubMed  PubMed Central  Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370

    Article  CAS  PubMed  Google Scholar 

  • Tan S, Wang Y, Chen K, Long Z, Zou J (2017) Ketamine alleviates depressive-like behaviors via down-regulating inflammatory cytokines induced by chronic restraint stress in mice. Biol Pharm Bull 40:1260–1267

    Article  CAS  PubMed  Google Scholar 

  • Wang DQ, Wang W, Jing FC (2007) Effects of tetramethylpyrazine on brain oxidative damage induced by intracerebral perfusion of L-DOPA in rats with Parkinson’s disease. Zhongguo Zhong Xi Yi Jie He Za Zhi 27:629–632

    PubMed  Google Scholar 

  • Wang C, He L, Yan M, Zheng GY, Liu XY (2014a) Effects of polyprenols from pine needles of Pinus massoniana on ameliorating cognitive impairment in a D-galactose-induced mouse model. AGE 36:9676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Z, Zhang Q, Yuan L, Wang S, Liu L, Yang X, Li G, Liu D (2014b) The effects of curcumin on depressive-like behavior in mice after lipopolysaccharide administration. Behav Brain Res 274:282–290

    Article  CAS  PubMed  Google Scholar 

  • Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134:319–329

    Article  CAS  PubMed  Google Scholar 

  • Wohleb ES, Franklin T, Iwata M, Duman RS (2016) Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci 17:497–511

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Wang H, Chavan SS, Andersson U (2015) High mobility group box protein 1 (HMGB1): the prototypical endogenous danger molecule. Mol Med 21(Suppl 1):S6–S12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yazir Y, Utkan T, Gacar N, Aricioglu F (2015) Resveratrol exerts anti-inflammatory and neuroprotective effects to prevent memory deficits in rats exposed to chronic unpredictable mild stress. Physiol Behav 138:297–304

    Article  CAS  PubMed  Google Scholar 

  • Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, Hashimoto K (2017) Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut-microbiota-brain axis. Transl Psychiatry 7:e1138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang HX, Xu YQ, Li YY, Lu MF, Shi SX, Ji JL, Wang LW (2018) Difference in proinflammatory cytokines produced by monocytes between patients with major depressive disorder and healthy controls. J Affect Disord 234:305–310

    Article  CAS  PubMed  Google Scholar 

  • Zhou Z, Wang Z, Guan Q, Qiu F, Li Y, Liu Z, Zhang H, Dong H, Zhang Z (2016) PEDF inhibits the activation of NLRP3 inflammasome in hypoxia cardiomyocytes through PEDF receptor/phospholipase A2. Int J Mol Sci 17

  • Zhou XY, Zhang F, Hu XT, Chen J, Tang RX, Zheng KY, Song YJ (2017) Depression can be prevented by astaxanthin through inhibition of hippocampal inflammation in diabetic mice. Brain Res 1657:262–268

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the Priority Academic Program Development of Xinjiang Higher Education Institutions.

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  1. Songnian Fu and Jiangtao Wang contributed equally to this work.

Authors and Affiliations

  1. Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China

    Songnian Fu, Jiangtao Wang & Haihong Dang

  2. Department of Neurology, The First Affiliated Hospital Xinjiang Medical University, Urumqi, Xinjiang Province, China

    Chenguang Hao

  3. Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Li Yu Shan South Road, No. 137, Urumqi, 830054, Xinjiang, People’s Republic of China

    Sheng Jiang

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  1. Songnian Fu
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Contributions

Author Songnian Fu and Sheng Jiang designed the study and wrote the protocol. Author Songnian Fu and Jiangtao Wang managed the literature searches and analyses. Authors Chenguang Hao and Haihong Dang undertook the statistical analysis, and author Songnian Fu wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

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Correspondence to Sheng Jiang.

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All animal experiments were approved by the Animal Experimentation Ethics Committee (AEEC) of Xinjiang Medical University, which in accordance with the “Guide and Care and Use of Laboratory Animals” (National Institutes of Health).

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Fu, S., Wang, J., Hao, C. et al. Tetramethylpyrazine ameliorates depression by inhibiting TLR4-NLRP3 inflammasome signal pathway in mice. Psychopharmacology 236, 2173–2185 (2019). https://doi.org/10.1007/s00213-019-05210-6

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