Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Psychiatry
Published in: BMC Psychiatry 1/2023

Open Access 01-12-2023 | Minocycline | Research

Minocycline and antipsychotics inhibit inflammatory responses in BV-2 microglia activated by LPS via regulating the MAPKs/ JAK-STAT signaling pathway

Authors: Yujun Long, Ying Wang, Yidong Shen, Jing Huang, Yamin Li, Renrong Wu, Jingping Zhao

Published in: BMC Psychiatry | Issue 1/2023

Login to get access

Abstract

Background

Abnormal activation of microglia is involved in the pathogenesis of schizophrenia. Minocycline and antipsychotics have been reported to be effective in inhibiting the activation of microglia and thus alleviating the negative symptoms of patients with schizophrenia. However, the specific molecular mechanism by which minocycline and antipsychotics inhibit microglial activation is not clear. In this study, we aimed to explore the molecular mechanism of treatment effect of minocycline and antipsychotics on schizophrenia.

Methods

Microglia cells were activated by lipopolysaccharide (LPS) and further treated with minocycline, haloperidol, and risperidone. Then cell morphology, specific marker, cytokines, and nitric oxide production process, and the proteins in related molecular signaling pathways in LPS-activated microglia were compared among groups.

Results

The study found that minocycline, risperidone, and haloperidol significantly inhibited morphological changes and reduced the expression of OX-42 protein induced by LPS. Minocycline significantly decreased the production of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β). Risperidone also showed significant decrease in the production of IL-6 and TNF-α, while haloperidol only showed significant decrease in the production of IL-6. Minocycline, risperidone, and haloperidol were found to significantly inhibit nitric oxide (NO) expression, but had no effect on inducible nitric oxide synthase (iNOS) expression. Both minocycline and risperidone were effective in decreasing the activity of c‑Jun N‑terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in the mitogen-activated protein kinases (MAPKs) signal pathway. Additionally, minocycline and risperidone were found to increase the activity of phosphorylated-p38. In contrast, haloperidol only suppressed the activity of ERK. Minocycline also suppressed the activation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), while risperidone and haloperidol only suppressed the activation of STAT3.

Conclusions

The results demonstrated that minocycline and risperidone exert stronger anti-inflammatory and neuroprotective effects stronger than haloperidol, through MAPKs and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways in BV2 cells stimulated with LPS, revealing the underlying mechanisms of minocycline and atypical antipsychotics in the treatment of negative schizophrenia symptoms.
Appendix
Available only for authorised users
Literature
1.
2.
Andrea Grostøl Dietz SAG, Maiken Nedergaard. Glial cells in schizophrenia: a unified hypothesis. Lancet Psychiatry. 2020;7(3):272–81.CrossRef
3.
Laskaris LE, Everall MADBI, Christopoulos GChanaA, Skafidas E. VLCropley and C Pantelis. Microglial activation and progressive brain changes in schizophrenia. Br J Pharmacol 2016; (173):666–80.
4.
De Picker LJ, Morrens M, Chance SA, Boche D. Microglia and Brain plasticity in Acute psychosis and Schizophrenia Illness Course: a Meta-review. Front Psychiatry. 2017;8:238.CrossRefPubMedPubMedCentral
5.
Rodrigues-Neves AC, Ambrósio AF, Gomes CA. Microglia sequelae: brain signature of innate immunity in schizophrenia. Transl Psychiatry. 2022;12(1):493.CrossRefPubMedPubMedCentral
6.
Al-Samhari MM, Al-Rasheed NM, Al-Rejaie S, Al-Rasheed NM, Hasan IH, Mahmoud AM, et al. Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine-mediated antidepressant-like effects. Exp Biol Med (Maywood). 2016;241(5):509–18.CrossRefPubMed
7.
Nicolas CS, Peineau S, Amici M, Csaba Z, Fafouri A, Javalet C, et al. The Jak/STAT pathway is involved in synaptic plasticity. Neuron. 2012;73:374–90.CrossRefPubMedPubMedCentral
8.
Shariq AS, Brietzke E, Rosenblat JD, Pan Z, Rong C, Ragguett RM, et al. Therapeutic potential of JAK/STAT pathway modulation in mood disorders. Rev Neurosci. 2018;30(1):1–7.CrossRefPubMed
9.
Zhang J, He H, Qiao Y, Zhou T, He H, Yi S, et al. Priming of microglia with IFN-gamma impairs adult hippocampal neurogenesis and leads to depression-like behaviors and cognitive defects. Glia. 2020;68(12):2674–92.CrossRefPubMed
10.
MacDowell KS, Garcia-Bueno B, Madrigal JL, Parellada M, Arango C, Mico JA, et al. Risperidone normalizes increased inflammatory parameters and restores anti-inflammatory pathways in a model of neuroinflammation. Int J Neuropsychopharmacol. 2013;16(1):121–35.CrossRefPubMed
11.
Tiina Tikka BLF, Gundars, Goldsteins. Riitta Keina¨nen, and Jari Koistinaho. Minocycline, a Tetracycline Derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of Microglia. J Neurosci. 2001;21(8):2580–88.CrossRefPubMedCentral
12.
Naura AS, Kim H, Ju J, Rodriguez PC, Jordan J, Catling AD, et al. Minocycline blocks asthma-associated inflammation in part by interfering with the T cell receptor-nuclear factor kappaB-GATA-3-IL-4 axis without a prominent effect on poly(ADP-ribose) polymerase. J Biol Chem. 2013;288(3):1458–68.CrossRefPubMed
13.
Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol. 2012;26(9):1185–93.CrossRefPubMed
14.
Shin H, Song JH. Antipsychotics, chlorpromazine and haloperidol inhibit voltage-gated proton currents in BV2 microglial cells. Eur J Pharmacol. 2014;738:256–62.CrossRefPubMed
15.
Bian Q, Kato T, Monji A, Hashioka S, Mizoguchi Y, Horikawa H, et al. The effect of atypical antipsychotics, perospirone, ziprasidone and quetiapine on microglial activation induced by interferon-gamma. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):42–8.CrossRefPubMed
16.
Zhu F, Zheng Y, Ding YQ, Liu Y, Zhang X, Wu R, et al. Minocycline and risperidone prevent microglia activation and rescue behavioral deficits induced by neonatal intrahippocampal injection of lipopolysaccharide in rats. PLoS ONE. 2014;9(4):e93966.CrossRefPubMedPubMedCentral
17.
Zhu F, Zheng Y, Liu Y, Zhang X, Zhao J. Minocycline alleviates behavioral deficits and inhibits microglial activation in the offspring of pregnant mice after administration of polyriboinosinic-polyribocytidilic acid. Psychiatry Res. 2014;219(3):680–6.CrossRefPubMed
18.
Kato T, Monji A, Hashioka S, Kanba S. Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro. Schizophr Res. 2007;92(1–3):108–15.CrossRefPubMed
19.
Kato TA, Monji A, Mizoguchi Y, Hashioka S, Horikawa H, Seki Y, et al. Anti-inflammatory properties of antipsychotics via microglia modulations: are antipsychotics a ‘fire extinguisher’ in the brain of schizophrenia? Mini Rev Med Chem. 2011;11(7):565–74.CrossRefPubMed
20.
Caruso G, Grasso M, Fidilio A, Tascedda F, Drago F, Caraci F. Antioxidant Properties of Second-Generation Antipsychotics: Focus on Microglia. Pharmaceuticals (Basel). 2020; 13(12).
21.
Xiang YQ, Zheng W, Wang SB, Yang XH, Cai DB, Ng CH, et al. Adjunctive minocycline for schizophrenia: a meta-analysis of randomized controlled trials. Eur Neuropsychopharmacol. 2017;27(1):8–18.CrossRefPubMed
22.
Zhu L, Liu X, Nemeth DP, DiSabato DJ, Witcher KG, McKim DB, et al. Interleukin-1 causes CNS inflammatory cytokine expression via endothelia-microglia bi-cellular signaling. Brain Behav Immun. 2019;81:292–304.CrossRefPubMedPubMedCentral
23.
Kato TA, Monji A, Yasukawa K, Mizoguchi Y, Horikawa H, Seki Y, et al. Aripiprazole inhibits superoxide generation from phorbol-myristate-acetate (PMA)-stimulated microglia in vitro: implication for antioxidative psychotropic actions via microglia. Schizophr Res. 2011;129(2–3):172–82.CrossRefPubMed
24.
Sugino H, Futamura T, Mitsumoto Y, Maeda K, Marunaka Y. Atypical antipsychotics suppress production of proinflammatory cytokines and up-regulate interleukin-10 in lipopolysaccharide-treated mice. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(2):303–7.CrossRefPubMed
25.
Kowalski J, Labuzek K, Herman ZS. Flupentixol and trifluperidol reduce secretion of tumor necrosis factor-alpha and nitric oxide by rat microglial cells. Neurochem Int. 2003;43(2):173–8.CrossRefPubMed
26.
Kowalski J, Labuzek K, Herman ZS. Flupentixol and trifluperidol reduce interleukin-1 beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Pol J Pharmacol. 2004;56(5):563–70.PubMed
27.
Labuzek K, Kowalski J, Gabryel B, Herman ZS. Chlorpromazine and loxapine reduce interleukin-1beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Eur Neuropsychopharmacol. 2005;15:23–30.CrossRefPubMed
28.
Abrantes A, Giusti-Rodriguez P, Ancalade N, Sekle S, Basiri ML, Stuber GD, et al. Gene expression changes following chronic antipsychotic exposure in single cells from mouse striatum. Mol Psychiatry. 2022;27(6):2803–12.CrossRefPubMed
29.
Racki V, Marcelic M, Stimac I, Petric D, Kucic N. Effects of Haloperidol, Risperidone, and Aripiprazole on the Immunometabolic Properties of BV-2 microglial cells. Int J Mol Sci. 2021; 22(9).
30.
Mayer B, Schmidt K, Humbert P. Biosynthesis of endotheliumderived relaxing factor: a cytosolic enzyme in porcine aortic endothelial cells Ca2+-dependently converts L-arginine into an activator of soluble guanylyl cyclase. Biochem Biophys Res Commun. 1989;164:678–85.CrossRefPubMed
31.
Yanik MVH, Kocyigit A, Tutkun H, Zoroglu SS, Herken H. Is the arginine-nitric oxide pathway involved in the pathogenesis of schizophrenia? Neuropsychobiology. 2003;47:61–5.CrossRefPubMed
32.
Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE Jr. Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development. Arch Gen Psychiatry. 1993;50:178–87.CrossRefPubMed
33.
Romero-Miguel D, Casquero-Veiga M, MacDowell KS, Torres-Sanchez S, Garcia-Partida JA, Lamanna-Rama N, et al. A characterization of the Effects of Minocycline Treatment during Adolescence on Structural, metabolic, and oxidative stress parameters in a maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders. Int J Neuropsychopharmacol. 2021;24(9):734–48.CrossRefPubMedPubMedCentral
34.
Hou Y, Wu CF, Yang JY, He X, Bi XL, Yu L, et al. Effects of clozapine, olanzapine and haloperidol on nitric oxide production by lipopolysaccharide-activated N9 cells. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(8):1523–8.CrossRefPubMed
35.
Bodles AM, Barger SW. Secreted beta-amyloid precursor protein activates microglia via JNK and p38-MAPK. Neurobiol Aging. 2005;26(1):9–16.CrossRefPubMed
36.
Hua Fan P-FW, Zhang L, Wen Z-LH, Guan WXin-Lei, Luo H, Ni M, Yang J-W, Li M-X, Chen J-G. Fang Methionine Sulfoxide reductase A negatively controls Microglia-mediated Neuroinflammation via inhibiting ROS/MAPKs/NF-κB signaling pathways through a Catalytic antioxidant function. Volume 22. ANTIOXIDANTS & REDOX SIGNALING; 2015. pp. 832–47. 10.
37.
Wang X, Hu D, Zhang L, Lian G, Zhao S, Wang C, et al. Gomisin A inhibits lipopolysaccharide-induced inflammatory responses in N9 microglia via blocking the NF-kappaB/MAPKs pathway. Food Chem Toxicol. 2014;63:119–27.CrossRefPubMed
38.
Huang C, Ma R, Sun S, Wei G, Fang Y, Liu R, et al. JAK2-STAT3 signaling pathway mediates thrombin-induced proinflammatory actions of microglia in vitro. J Neuroimmunol. 2008;204(1–2):118–25.CrossRefPubMed
39.
Kim OS, Park EJ, Joe EH, Jou I. JAK-STAT signaling mediates gangliosides-induced inflammatory responses in brain microglial cells. J Biol Chem. 2002;277(43):40594–601.CrossRefPubMed
Metadata
Title
Minocycline and antipsychotics inhibit inflammatory responses in BV-2 microglia activated by LPS via regulating the MAPKs/ JAK-STAT signaling pathway
Authors
Yujun Long
Ying Wang
Yidong Shen
Jing Huang
Yamin Li
Renrong Wu
Jingping Zhao
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Psychiatry / Issue 1/2023
Electronic ISSN: 1471-244X
DOI
https://doi.org/10.1186/s12888-023-05014-1

Other articles of this Issue 1/2023

BMC Psychiatry 1/2023 Go to the issue

Research

Association between age and loneliness in different residential type and gender groups: evidence from China

Study protocol

Eye movement desensitization and reprocessing (EMDR) therapy or supportive counseling prior to exposure therapy in patients with panic disorder: study protocol for a multicenter randomized controlled trial (IMPROVE)

Research

Loneliness in the Norwegian adolescent population: prevalence trends and relations to mental and self-rated health

Research

Impact of COVID-19 on electroconvulsive therapy practice across Canadian provinces during the first wave of the pandemic

Research

Exploring negative symptoms heterogeneity in patients diagnosed with schizophrenia and schizoaffective disorder using cluster analysis

Research

Management practice and discharge outcome of patients with psychiatric disorder admitted to psychiatry wards of selected specialized settings in Ethiopia