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Intranasal Monophosphoryl Lipid a Administration Ameliorates depression-like Behavior in Chronically Stressed Mice Through Stimulation of Microglia

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Abstract

We and others have reported that systematic stimulation of the central innate immune system by a low dose of lipopolysaccharide (LPS) can improve depression-like behavior in chronically stressed animals. However, it is unclear whether similar stimulation by intranasal administration could improve depression-like behavior in animals. We investigated this question using monophosphoryl lipid A (MPL), a derivative of LPS that lacks the adverse effects of LPS but is still immuno-stimulatory. We found that a single intranasal administration of MPL at a dose of 10 or 20 µg/mouse, but not at a dose of 5 µg/mouse, ameliorated chronic unpredictable stress (CUS)-induced depression-like behavior in mice, as evidenced by the decrease in immobility time in tail suspension test and forced swimming test and the increase in sucrose intake in sucrose preference test. In the time-dependent analysis, the antidepressant-like effect of a single intranasal MPL administration (20 µg/mouse) was observed 5 and 8 h but not 3 h after drug administration and persisted for at least 7 days. Fourteen days after the first intranasal MPL administration, a second intranasal MPL administration (20 µg/mouse) still showed an antidepressant-like effect. The innate immune response mediated by microglia might mediate the antidepressant-like effect of intranasal MPL administration, because both inhibition of microglial activation by pretreatment with minocycline and depletion of microglia by pretreatment with PLX3397 prevented the antidepressant-like effect of intranasal MPL administration. These results suggest that intranasal administration of MPL can produce significant antidepressant-like effects in animals under chronic stress conditions via stimulation of microglia.

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References

  1. Dobrek L, Głowacka K (2023) Depression and its phytopharmacotherapy-a narrative review. Int J Mol Sci 24:4772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Vahid-Ansari F, Albert PR (2021) Rewiring of the serotonin system in major depression. Front Psychiatr 12:802581

    Article  Google Scholar 

  3. Winter J, Curtis K, Hu B, Clayton AH (2022) Sexual dysfunction with major depressive disorder and antidepressant treatments: impact, assessment, and management. Expert Opin Drug Saf 21:913–930

    Article  PubMed  Google Scholar 

  4. Brietzke E, Vazquez GH, Kang MJY, Soares CN (2019) Pharmacological treatment for insomnia in patients with major depressive disorder. Expert Opin Pharmacother 20:1341–1349

    Article  CAS  PubMed  Google Scholar 

  5. Möller HJ, Baldwin DS, Goodwin G, Kasper S, Okasha A, Stein DJ, Tandon R, Versiani M, WPA Section on Pharmacopsychiatry (2008) Do SSRIs or antidepressants in general increase suicidality? WPA Section on pharmacopsychiatry: consensus statement. Eur Arch Psychiatry Clin Neurosci 258(Suppl 3):3–23

    Article  PubMed  Google Scholar 

  6. Wang H, He Y, Sun Z, Ren S, Liu M, Wang G, Yang J (2022) Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression. J Neuroinflamm 19:132

    Article  Google Scholar 

  7. Nieto-Quero A, Chaves-Peña P, Santín LJ, Pérez-Martín M, Pedraza C (2021) Do changes in microglial status underlie neurogenesis impairments and depressive-like behaviours induced by psychological stress? a systematic review in animal models. Neurobiol Stress 15:100356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tartt AN, Mariani MB, Hen R, Mann JJ, Boldrini M (2022) Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol Psychiatr 27:2689–2699

    Article  CAS  Google Scholar 

  9. Xia CY, Guo YX, Lian WW, Yan Y, Ma BZ, Cheng YC, Xu JK, He J, Zhang WK (2023) The NLRP3 inflammasome in depression: potential mechanisms and therapies. Pharmacol Res 187:106625

    Article  CAS  PubMed  Google Scholar 

  10. Chung YC, Kim SR, Park JY, Chung ES, Park KW, Won SY, Bok E, Jin M, Park ES, Yoon SH, Ko HW, Kim YS, Jin BK (2011) Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. Neuropharmacology 60:963–974

    Article  CAS  PubMed  Google Scholar 

  11. Shi M, Mi L, Li F, Li Y, Zhou Y, Chen F, Liu L, Chai Y, Yang W, Zhang J, Chen X (2022) Fluvoxamine confers neuroprotection via inhibiting infiltration of peripheral leukocytes and M1 polarization of microglia/macrophages in a mouse model of traumatic brain Injury. J Neurotrauma 39:1240–1261

    Article  PubMed  Google Scholar 

  12. Almeida OP, Norman PE, Allcock R, van Bockxmeer F, Hankey GJ, Jamrozik K, Flicker L (2009) Polymorphisms of the CRP gene inhibit inflammatory response and increase susceptibility to depression: the health in men Study. Int J Epidemiol 38:1049–1059

    Article  PubMed  PubMed Central  Google Scholar 

  13. Carboni L, Becchi S, Piubelli C, Mallei A, Giambelli R, Razzoli M, Mathé AA, Popoli M, Domenici E (2010) Early-life stress and antidepressants modulate peripheral biomarkers in a gene-environment rat model of depression. Prog Neuropsychopharmacol Biol Psychiatr 34:1037–1048

    Article  CAS  Google Scholar 

  14. Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P (2011) Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A 108:9262–9267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tong L, Gong Y, Wang P, Hu W, Wang J, Chen Z, Zhang W, Huang C (2017) Microglia loss contributes to the development of major depression Induced by different types of chronic stresses. Neurochem Res 42:2698–2711

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. Cai Z, Ye T, Xu X, Gao M, Zhang Y, Wang D, Gu Y, Zhu H, Tong L, Lu J, Chen Z, Huang C (2020) Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress. Prog Neuropsychopharmacol Biol Psychiatry 101:109931

    Article  CAS  PubMed  Google Scholar 

  18. Loftus LT, Li HF, Gray AJ, Hirata-Fukae C, Stoica BA, Futami J, Yamada H, Aisen PS, Matsuoka Y (2006) In vivo protein transduction to the CNS. Neuroscience 139:1061–1067

    Article  CAS  PubMed  Google Scholar 

  19. Illum L (2004) Is nose-to-brain transport of drugs in man a reality? J Pharm Pharmacol 56:3–17

    Article  CAS  PubMed  Google Scholar 

  20. Hagen SR, Thompson JD, Snyder DS, Myers KR (1997) Analysis of a monophosphoryl lipid a immunostimulant preparation from Salmonella minnesota R595 by high-performance liquid chromatography. J Chromatogr A 767:53–61

    Article  CAS  PubMed  Google Scholar 

  21. Schülke S, Flaczyk A, Vogel L, Gaudenzio N, Angers I, Löschner B, Wolfheimer S, Spreitzer I, Qureshi S, Tsai M, Galli S, Vieths S, Scheurer S (2015) MPLA shows attenuated pro-inflammatory properties and diminished capacity to activate mast cells in comparison with LPS. Allergy 70:1259–1268

    Article  PubMed  Google Scholar 

  22. Bohannon JK, Hernandez A, Enkhbaatar P, Adams WL, Sherwood ER (2013) The immunobiology of toll-like receptor 4 agonists: from endotoxin tolerance to immunoadjuvants. Shock 40:451–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hosseini SM, Gholami Pourbadie H, Sayyah M, Zibaii MI, Naderi N (2018) Neuroprotective effect of monophosphoryl lipid A, a detoxified lipid a derivative, in photothrombotic model of unilateral selective hippocampal ischemia in rat. Behav Brain Res 347:26–36

    Article  CAS  PubMed  Google Scholar 

  24. Li F, Xiang H, Gu Y, Ye T, Lu X, Huang C (2022) Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice. J Neuroinflammation 19:12

    Article  PubMed  PubMed Central  Google Scholar 

  25. Li F, Lu X, Ma Y, Gu Y, Ye T, Huang C (2022) Monophosphoryl lipid a tolerance against chronic stress-induced depression-like behaviors in mice. Int J Neuropsychopharmacol 25:399–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yousefi N, Sotoodehnejadnematalahi F, Heshmati-Fakhr N, Sayyah M, Hoseini M, Ghassemi S, Aliakbari S, Pourbadie HG (2019) Prestimulation of microglia through TLR4 pathway promotes interferon beta expression in a rat model of alzheimer’s disease. J Mol Neurosci 67:495–503

    Article  CAS  PubMed  Google Scholar 

  27. KleinJan A, Willart M, van Rijt LS, Braunstahl GJ, Leman K, Jung S, Hoogsteden HC, Lambrecht BN (2006) An essential role for dendritic cells in human and experimental allergic rhinitis. J Allergy Clin Immunol 118:1117–1125

    Article  CAS  PubMed  Google Scholar 

  28. Mika J, Wawrzczak-Bargiela A, Osikowicz M, Makuch W, Przewlocka B (2009) Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice. Brain Behav Immun 23:75–84

    Article  CAS  PubMed  Google Scholar 

  29. Gu Y, Ye T, Tan P, Tong L, Ji J, Gu Y, Shen Z, Shen X, Lu X, Huang C (2021) Tolerance-inducing effect and properties of innate immune stimulation on chronic stress-induced behavioral abnormalities in mice. Brain Behav Immun 91:451–471

    Article  CAS  PubMed  Google Scholar 

  30. Dantzer R (2009) Cytokine, sickness behavior, and depression. Immunol Allergy Clin North Am 29:247–264

    Article  PubMed  PubMed Central  Google Scholar 

  31. Venezia S, Refolo V, Polissidis A, Stefanis L, Wenning GK, Stefanova N (2017) Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal α-synucleinopathy. Mol Neurodegener 12:52

    Article  PubMed  PubMed Central  Google Scholar 

  32. Michaud JP, Hallé M, Lampron A, Thériault P, Préfontaine P, Filali M, Tribout-Jover P, Lanteigne AM, Jodoin R, Cluff C, Brichard V, Palmantier R, Pilorget A, Larocque D, Rivest S (2013) Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves alzheimer’s disease-related pathology. Proc Natl Acad Sci 110:1941–1946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Martins-Ferreira R, Leal B, Costa PP, Ballestar E (2021) Microglial innate memory and epigenetic reprogramming in neurological disorders. Prog Neurobiol 200:101971

    Article  CAS  PubMed  Google Scholar 

  34. Jeon SW, Kim YK (2023) Neuron-microglia crosstalk in neuropsychiatric disorders. Adv Exp Med Biol 1411:3–15

    Article  PubMed  Google Scholar 

  35. Koss K, Churchward MA, Tsui C, Todd KG (2019) In vitro priming and hyper-activation of brain microglia: an assessment of phenotypes. Mol Neurobiol 56:6409–6425

    Article  CAS  PubMed  Google Scholar 

  36. Wu Z, Zhou L, Sun L, Xie Y, Xiao L, Wang H, Wang G (2021) Brief postpartum separation from offspring promotes resilience to lipopolysaccharide challenge-induced anxiety and depressive-like behaviors and inhibits neuroinflammation in C57BL/6J dams. Brain Behav Immun 95:190–202

    Article  CAS  PubMed  Google Scholar 

  37. Wohleb ES, Fenn AM, Pacenta AM, Powell ND, Sheridan JF, Godbout JP (2012) Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology 37:1491–1505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Azimi A, Heidarian S, Zamani H, Taleghani N, Dehghani M, Seyedjafari E (2020) Optimized dose of synthetic analogues of monophosphoryl lipid A as an effective alternative for formulating recombinant human papillomavirus vaccine. Biologicals 68:60–64

    Article  CAS  PubMed  Google Scholar 

  39. He Z, Yang Y, Xing Z, Zuo Z, Wang R, Gu H, Qi F, Yao Z (2020) Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice. Cell Death Dis 11:440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rimmerman N, Verdiger H, Goldenberg H, Naggan L, Robinson E, Kozela E, Gelb S, Reshef R, Ryan KM, Ayoun L, Refaeli R, Ashkenazi E, Schottlender N, Ben Hemo-Cohen L, Pienica C, Aharonian M, Dinur E, Lazar K, McLoughlin DM, Zvi AB, Yirmiya R (2022) Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation. Mol Psychiatr 27:1120–1135

    Article  CAS  Google Scholar 

  41. Pereira CPM, Francis-Oliveira J, Singulani MP, Ferreira AFF, Britto LRG (2023) Microglial depletion exacerbates motor impairment and dopaminergic neuron loss in a 6-OHDA model of parkinson’s disease. J Neuroimmunol 375:578019

    Article  CAS  PubMed  Google Scholar 

  42. Radpour M, Choopani S, Pourbadie HG, Sayyah M (2022) Activating toll-like receptor 4 after traumatic brain injury inhibits neuroinflammation and the accelerated development of seizures in rats. Exp Neurol 357:114202

    Article  CAS  PubMed  Google Scholar 

  43. Guo X, Du L, Ma N, Zhang P, Wang Y, Han Y, Huang X, Zhang Q, Tan X, Lei X, Qu B (2022) Monophosphoryl lipid A ameliorates radiation-induced lung injury by promoting the polarization of macrophages to the M1 phenotype. J Transl Med 20:597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sun X, Hosomi K, Shimoyama A, Yoshii K, Lan H, Wang Y, Yamaura H, Nagatake T, Ishii KJ, Akira S, Kiyono H, Fukase K, Kunisawa J (2023) TLR4 agonist activity of alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells. Int Immunopharmacol 117:109852

    Article  CAS  PubMed  Google Scholar 

  45. Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, Yin X, Kidd GJ, Bergmann CC, Stohlman SA, Trapp BD (2012) Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci 32:11706–11715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li T, Zhao J, Xie W, Yuan W, Guo J, Pang S, Gan WB, Gómez-Nicola D, Zhang S (2021) Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage. J Neuroinflammation 18:81

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wu W, Li Y, Wei Y, Bosco DB, Xie M, Zhao MG, Richardson JR, Wu LJ (2020) Microglial depletion aggravates the severity of acute and chronic seizures in mice. Brain Behav Immun 89:245–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Delpech JC, Saucisse N, Parkes SL, Lacabanne C, Aubert A, Casenave F, Coutureau E, Sans N, Layé S, Ferreira G, Nadjar A (2015) Microglial activation enhances associative taste memory through purinergic modulation of glutamatergic neurotransmission. J Neurosci 35:3022–3033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A (2012) Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci A109:E197–E205

    Google Scholar 

  50. Aleksandrova LR, Phillips AG, Wang YT (2017) Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. J Psychiatr Neurosci 42:222–229

    Article  Google Scholar 

  51. Yu H, Li M, Zhou D, Lv D, Liao Q, Lou Z, Shen M, Wang Z, Li M, Xiao X, Zhang Y, Wang C (2018) Vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release and membrane GluA1 activation is involved in the rapid antidepressant-like effects of scopolamine in mice. Neuropharmacology 131:209–222

    Article  CAS  PubMed  Google Scholar 

  52. Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, Fang YY, Zhang J, Li SJ, Xiong WC, Yan HC, Gao YB, Liu JH, Li XW, Sun LR, Zeng YN, Zhu XH, Gao TM (2013) Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med 19:773–777

    Article  CAS  PubMed  Google Scholar 

  53. Heinsbroek RP, Van Haaren F, Van de Poll NE, Steenbergen HL (1991) Sex differences in the behavioral consequences of inescapable footshocks depend on time since shock. Physiol Behav 49:1257–1263

    Article  CAS  PubMed  Google Scholar 

  54. Viau V, Bingham B, Davis J, Lee P, Wong M (2005) Gender and puberty interact on the stress-induced activation of parvocellular neurosecretory neurons and corticotropin-releasing hormone messenger ribonucleic acid expression in the rat. Endocrinology 146:137–146

    Article  CAS  PubMed  Google Scholar 

  55. Tonelli LH, Holmes A, Postolache TT (2008) Intranasal immune challenge induces sex-dependent depressive-like behavior and cytokine expression in the brain. Neuropsychopharmacology 33:1038–1048

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would kindly like to thank Dr Yiming Gu for his initial contribution to the construction of the depression model.

Funding

This work was supported by the Innovation and Entrepreneurship Training Program for College Students in Jiangsu Province (202210304158Y), the Postgraduate Research and Practice Innovation Program of Jiangsu Province (KYCX20-2855), the Natural Science Foundation of China (81974216), the Natural Science Foundation of Jiangsu Province (BK20221375), and the Six Phase of Jiangsu 333 High-Level Talent Training Project (2022: 3-16-661).

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Author notes

  1. Meng Zheng, Tao Zhu and Bingran Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu Province, China

    Meng Zheng, Tao Zhu, Bingran Chen, Hui Zhao, Xu Lu, Han Han, Ting Ye & Chao Huang

  2. Department of Pharmacy, Nantong Third Hospital Affiliated to Nantong University, #60 Middle Qingnian Road, Nantong, 226006, Jiangsu, China

    Qun Lu

  3. Department of Pharmacy, Changzhou Geriatric Hospital Affiliated to Soochow University, Changzhou No.7 People’s Hospital, 288# Yanling East Road, Changzhou, 213000, Jiangsu, China

    Mingxie Ni & Li Cheng

  4. Department of Ultrasound, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong, 226001, Jiangsu, China

    Ying Ye

  5. Department of Pharmacy, The First People’s Hospital of Yancheng, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, #66 Renmin South Road, Yancheng, 224006, Jiangsu, China

    Huijun Liu

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  1. Meng Zheng
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Contributions

MZ: Methodology, Software, Investigation, Formal analysis, Writing—original draft. TZ: Methodology, Investigation, Formal analysis. BC: Visualization, Investigation. HZ: Methodology, Software, Investigation, Formal analysis, Data curation. XL: Resources, Supervision. QL: Methodology. MN: Methodology. LC: Methodology. HH: Methodology, Investigation, Formal analysis. TY: Methodology. YY: Methodology. HL: Conceptualization, Resources, Supervision. CH: Conceptualization, Resources, Supervision. All authors reviewed and approved the manuscript.

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Correspondence to Chao Huang.

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Zheng, M., Zhu, T., Chen, B. et al. Intranasal Monophosphoryl Lipid a Administration Ameliorates depression-like Behavior in Chronically Stressed Mice Through Stimulation of Microglia. Neurochem Res 48, 3160–3176 (2023). https://doi.org/10.1007/s11064-023-03974-0

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