Metabolic Brain Disease

, Volume 34, Issue 1, pp 319–329 | Cite as

Allicin attenuated chronic social defeat stress induced depressive-like behaviors through suppression of NLRP3 inflammasome

  • Wenqi Gao
  • Wei Wang
  • Gang Liu
  • Jing Zhang
  • Jian YangEmail author
  • Zhifang DengEmail author
Original Article


Allicin, one of the main biologically active compounds derived from garlic, was previously reported to possess multiple pharmacological activities. Whether allicin protected against chronic social defeat stress (CSDS) induced depressive-like behaviors remained unknown. Thus, our present study for the first time investigated the potential antidepressant effects and the mechanisms of allicin on the CSDS mice model. Thirty minutes before social defeat stress, allicin (2, 10, 50 mg/kg) was treated by intraperitoneal injection. The duration times of CSDS model establishment and allicin intervene were 10 days. Subsequently, the force swimming test (FST), social interaction test (SIT), and sucrose preference test (SPT) were applied for behavioral assessments. The levels of inflammation mediators were determined by commercial ELISA kits. The concentration of iron was tested, and relative protein expressions were measured by western blot. Oxidative stress and apoptosis markers were also detected by commercial kits and western blot. The behavioral defects induced by social defeat stress were obviously improved by allicin. Microglia activation, as well as inflammatory cytokines elevation in the hippocampus of CSDS also down-regulated by administration of allicin. Furthermore, content of iron and protein expressions of key components in iron metabolism were remarkably aberrant changed in the CSDS mice hippocampus, meanwhile, allicin ameliorated this phenomenon. Allicin decreased the production of reactive oxygen species (ROS), malondialdehyde (MDA), and protein carbonyl, and the protein expression of NOX4, as well as up-regulated the activities of superoxide dismutase (SOD) and Nrf2/HO-1 pathway. In addition, allicin attenuated the enhanced neuronal apoptosis. Finally, allicin supplementation inhibited the Nucleotide-binding oligomerization domain containing 3 (NLRP3) inflammasome hyperactivity, and the expressions of inflammasome components, such as ACS, caspase-1, and IL-1β in the hippocampus of CSDS mice. Allicin attenuated depressive-like behaviors of CSDS mice through reducing neuroinflammation, ameliorating iron abnromal accumulation, balacing oxidative stress, and attenuation neuronal apoptosis in the hippocampus via suppression of NLRP3 inflammasome.


Allicin Chronic social defeat stress Depressive-like behavior Neuroinflammation Iron homeostasis NLRP3 



Chronic social defeat stress


Sucrose preference test


Social interaction test


Force swimming test




Divalent metal trasporter-1


Ionized calcium-binding adapter molecular 1


Reactive oxygen species




Superoxide dismutase


NADPH oxidase


Nuclear factor erythroid 2-related factor 2


Heme oxygenase-1


Nucleotide-binding oligomerization domain containing 3





We gratefully acknowledge the National Natural Science Foundation of China (81470387) for the generous financial support.

Compliance with ethical standards

Competing interests

The authors declare that they have no competing interests.


  1. Alcocer-Gomez E et al (2014) NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav Immun 36:111–117CrossRefGoogle Scholar
  2. Alcocer-Gomez E et al (2016) Stress-induced depressive behaviors require a functional NLRP3 Inflammasome. Mol Neurobiol 53(7):4874–4882CrossRefGoogle Scholar
  3. Al-Hakeim HK, Al-Rammahi DA, Al-Dujaili AH (2015) IL-6, IL-18, sIL-2R, and TNFalpha proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation. J Affect Disord 182:106–114CrossRefGoogle Scholar
  4. Bale TL, Dorsa DM, Johnston CA (1995) Oxytocin receptor mRNA expression in the ventromedial hypothalamus during the estrous cycle. J Neurosci 15(1):5058–5064CrossRefGoogle Scholar
  5. Baumeister D, Ciufolini S, Mondelli V (2016) Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment? Psychopharmacology 233(9):1575–1589CrossRefGoogle Scholar
  6. Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, Yücel M, Gama CS, Dodd S, Dean B, Magalhães PVS, Amminger P, McGorry P, Malhi GS (2011) Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 35(3):804–817CrossRefGoogle Scholar
  7. Berton O, McClung C, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311(5762):864–868CrossRefGoogle Scholar
  8. Björkqvist K (2001) Social defeat as a stressor in humans. Physiol Behav 73(3):435–442CrossRefGoogle Scholar
  9. Boelaert JR, Crichton RR (2001) Inorganic biochemistry of iron metabolism :from molecular mechanisms to clinical consequences, 2nd edn. Wiley, Chichester, p 326Google Scholar
  10. Brittenham GM et al (2000) Clinical consequences of new insights in the pathophysiology of disorders of iron and heme metabolism. Hematology Am Soc Hematol Educ Program:39–50Google Scholar
  11. Chen W, Qi J, Feng F, Wang MD, Bao G, Wang T, Xiang M, Xie WF (2014) Neuroprotective effect of allicin against traumatic brain injury via Akt/endothelial nitric oxide synthase pathway-mediated anti-inflammatory and anti-oxidative activities. Neurochem Int 68:28–37CrossRefGoogle Scholar
  12. Chung LY (2006) The antioxidant properties of garlic compounds: allyl cysteine, alliin, allicin, and allyl disulfide. J Med Food 9(2):205–213CrossRefGoogle Scholar
  13. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67(5):446–457CrossRefGoogle Scholar
  14. Du RH, et al. (2016) Fluoxetine inhibits NLRP3 inflammasome activation: implication in depression. Int J Neuropsychopharmacol 19(9)Google Scholar
  15. Gaynes BN et al (2009) What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv 60(11):1439–1445CrossRefGoogle Scholar
  16. Guarda G, Zenger M, Yazdi AS, Schroder K, Ferrero I, Menu P, Tardivel A, Mattmann C, Tschopp J (2011) Differential expression of NLRP3 among hematopoietic cells. J Immunol 186(4):2529–2534CrossRefGoogle Scholar
  17. Gutiérrez-Lobos, Karin, et al. "The influence of age on the female/male ratio of treated incidence rates in depression." BMC Psychiatry 2.1(2002):3Google Scholar
  18. Hannestad J, DellaGioia N, Bloch M (2011) The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36(12):2452–2459CrossRefGoogle Scholar
  19. Howren MB, Lamkin DM, Suls J (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71(2):171–186CrossRefGoogle Scholar
  20. Jiang P, Guo Y, Dang R, Yang M, Liao D, Li H, Sun Z, Feng Q, Xu P (2017) Salvianolic acid B protects against lipopolysaccharide-induced behavioral deficits and neuroinflammatory response: involvement of autophagy and NLRP3 inflammasome. J Neuroinflammation 14(1):239CrossRefGoogle Scholar
  21. Jo EK, Kim JK, Shin DM, Sasakawa C (2016) Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol 13(2):148–159CrossRefGoogle Scholar
  22. 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 64:367–383CrossRefGoogle Scholar
  23. Kessler RC (2003) Epidemiology of women and depression. J Affect Disord 74(1):5–13CrossRefGoogle Scholar
  24. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS, National Comorbidity Survey Replication (2003) The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289(23):3095–3105CrossRefGoogle Scholar
  25. Kong X, Gong S, Su L, Li C, Kong Y (2017) Neuroprotective effects of allicin on ischemia-reperfusion brain injury. Oncotarget 8(61):104492–104507CrossRefGoogle Scholar
  26. Kruszewski M (2003) Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res 531(1–2):81–92CrossRefGoogle Scholar
  27. Lee P, Peng H, Gelbart T, Beutler E (2004) The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes. Proc Natl Acad Sci U S A 101(25):9263–9265CrossRefGoogle Scholar
  28. Li M, Li C, Yu H, Cai X, Shen X, Sun X, Wang J, Zhang Y, Wang C (2017) Lentivirus-mediated interleukin-1beta (IL-1beta) knock-down in the hippocampus alleviates lipopolysaccharide (LPS)-induced memory deficits and anxiety- and depression-like behaviors in mice. J Neuroinflammation 14(1):190CrossRefGoogle Scholar
  29. Lu X, Yang RR, Zhang JL, Wang P, Gong Y, Hu WF, Wu Y, Gao MH, Huang C (2018) Tauroursodeoxycholic acid produces antidepressant-like effects in a chronic unpredictable stress model of depression via attenuation of neuroinflammation, oxido-nitrosative stress, and endoplasmic reticulum stress. Fundam Clin Pharmacol 32:363–377CrossRefGoogle Scholar
  30. Meerlo P et al (1996) Long-term changes in open field behaviour following a single social defeat in rats can be reversed by sleep deprivation. Physiol Behav 60(1):115–119CrossRefGoogle Scholar
  31. Murray MJ, Murray AB, Murray MB, Murray CJ (1978) The adverse effect of iron repletion on the course of certain infections. Br Med J 2(6145):1113–1115CrossRefGoogle Scholar
  32. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T (2004) IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113(9):1271–1276CrossRefGoogle Scholar
  33. Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229(2):327–336PubMedGoogle Scholar
  34. Rathore KI, Redensek A, David S (2012) Iron homeostasis in astrocytes and microglia is differentially regulated by TNF-alpha and TGF-beta1. Glia 60(5):738–750CrossRefGoogle Scholar
  35. Richter K, Konzack A, Pihlajaniemi T, Heljasvaara R, Kietzmann T (2015) Redox-fibrosis: impact of TGFbeta1 on ROS generators, mediators and functional consequences. Redox Biol 6:344–352CrossRefGoogle Scholar
  36. Schiepers OJ, Wichers MC, Maes M (2005) Cytokines and major depression. Prog Neuro-Psychopharmacol Biol Psychiatry 29(2):201–217CrossRefGoogle Scholar
  37. Su WJ et al (2017) NLRP3 gene knockout blocks NF-kappaB and MAPK signaling pathway in CUMS-induced depression mouse model. Behav Brain Res 322(Pt A):1–8CrossRefGoogle Scholar
  38. Tang J, Yu W, Chen S, Gao Z, Xiao B (2018) Microglia polarization and endoplasmic reticulum stress in chronic social defeat stress induced depression mouse. Neurochem Res 43:985–994CrossRefGoogle Scholar
  39. Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR (2009) Oligodendrocytes and myelination: the role of iron. Glia 57(5):467–478CrossRefGoogle Scholar
  40. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9(4):519–525CrossRefGoogle Scholar
  41. Uher R, Tansey KE, Dew T, Maier W, Mors O, Hauser J, Dernovsek MZ, Henigsberg N, Souery D, Farmer A, McGuffin P (2014) An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry 171(12):1278–1286CrossRefGoogle Scholar
  42. Von Frijtag JC et al (2000) Defeat followed by individual housing results in long-term impaired reward- and cognition-related behaviours in rats. Behav Brain Res 117(1):137–146CrossRefGoogle Scholar
  43. Wang L, Wang W, Zhao M, Ma L, Li M (2008) Psychological stress induces dysregulation of iron metabolism in rat brain. Neuroscience 155(1):24–30CrossRefGoogle Scholar
  44. Ward, R.J. and R.R. Crichton, Metal-based neurodegeneration :from molecular mechanisms to therapeutic strategies. 2006, Chichester: J. Wiley & Sons 227Google Scholar
  45. Ward RJ, Crichton RR (eds) (2013) Metal-based neurodegeneration :from molecular mechanisms to therapeutic strategies, 2nd edn. John Wiley & Sons, ChichesterGoogle Scholar
  46. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13(10):1045–1060CrossRefGoogle Scholar
  47. Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJL, Vos T (2013) Global burden of disease attributable to mental and substance use disorders: findings from the global burden of disease study 2010. Lancet 382(9904):1575–1586CrossRefGoogle Scholar
  48. Xiang Q, Li XH, Yang B, Fang XX, Jia J, Ren J, Dong YC, Ou-Yang C, Wang GC (2017) Allicin attenuates tunicamycin-induced cognitive deficits in rats via its synaptic plasticity regulatory activity. Iran J Basic Med Sci 20(6):676–682PubMedPubMedCentralGoogle Scholar
  49. Yamawaki Y, Yoshioka N, Nozaki K, Ito H, Oda K, Harada K, Shirawachi S, Asano S, Aizawa H, Yamawaki S, Kanematsu T, Akagi H (2018) Sodium butyrate abolishes lipopolysaccharide-induced depression-like behaviors and hippocampal microglial activation in mice. Brain Res 1680:13–38CrossRefGoogle Scholar
  50. Yan HC et al (2010) Fuzi polysaccharide-1 produces antidepressant-like effects in mice. Int J Neuropsychopharmacol 13(5):623–633CrossRefGoogle Scholar
  51. Zhang Z, Zhang K, du X, Li Y (2012) Neuroprotection of desferrioxamine in lipopolysaccharide-induced nigrostriatal dopamine neuron degeneration. Mol Med Rep 5(2):562–566PubMedGoogle Scholar
  52. Zhang B et al (2015) Protective effects of allicin against ischemic stroke in a rat model of middle cerebral artery occlusion. Mol Med Rep 12(3)Google Scholar
  53. Zhang H, Wang P, Xue Y, Liu L, Li Z, Liu Y (2018) Allicin ameliorates cognitive impairment in APP/PS1 mice via suppressing oxidative stress by blocking JNK signaling pathways. Tissue Cell 50:89–95CrossRefGoogle Scholar
  54. Zhu JW et al (2012) Neuroprotective effects of allicin on spinal cord ischemia-reperfusion injury via improvement of mitochondrial function in rabbits. Neurochem Int 61(5):640–648CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Central Experimental Laboratory & Yichang Key Laboratory of Ischemic Cardiovascular and Cerebrovascular Disease Translational Medicine, The First College of Clinical Medical ScienceChina Three Gorges University & Yichang Central People’s HospitalYichangChina
  2. 2.Department of Pharmacology, School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
  3. 3.Department of Pharmacy, The First College of Clinical Medical ScienceChina Three Gorges University & Yichang Central People’s HospitalYichangChina

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