Cited by 183Neuroinflammation and Neurodegeneration MechanismsTryptophan and brain disordersNeuroscience and Neuropharmacology Research

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Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants

Hwang, Jaegyu, Zheng, Long Tai, Ock, Jiyeon, Lee, Maan Gee, Kim, Sang-Hyun, Lee, Ho-Won, Lee, Won-Ha, Park, Hae-Chul, Suk, Kyoungho·2008·Neuropharmacology

DOI 10.1016/j.neuropharm.2008.06.045

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Abstract

Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may contribute to neuronal cell death. Inhibition of glial activation may alleviate neurodegeneration under these conditions. In the present study, the antiinflammatory and neuroprotective effects of tricyclic antidepressants were investigated using cultured brain cells as a model. The results showed that clomipramine and imipramine significantly decreased the production of nitric oxide or tumor necrosis factor-alpha (TNF-alpha) in microglia and astrocyte cultures. Clomipramine and imipramine also attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1beta and TNF-alpha at mRNA levels. In addition, clomipramine and imipramine inhibited IkappaB degradation, nuclear translocation of the p65 subunit of NF-kappaB, and phosphorylation of p38 mitogen-activated protein kinase in the lipopolysaccharide-stimulated microglia cells. Moreover, clomipramine and imipramine were neuroprotective as the drugs reduced microglia-mediated neuroblastoma cell death in a microglia/neuron co-culture. Therefore, these results imply that clomipramine and imipramine have antiinflammatory and neuroprotective effects in the central nervous system by modulating glial activation.

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Background
Bioenergetics and synaptic plasticity as potential targets for individualizing treatment for depression
Price, J. B., Bronars, C. A., Erhardt, S., Cullen, K., Schwieler, L., Berk, M., Walder, K. R., McGee, S. L., Frye, M. A., & Tye, S. J. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.04.002 · Cited by 47
The effect of different antidepressant drugs of oxidative stress after lipopolysaccharide administration in mice
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“crosis factor (TNF-α) (Hwang et al., 2008; Horikawa et al., 2010; Liu et al., 2011); these effect are likely to benefit the liver against toxic injury.”
Background
Natural Flavone Jaceosidin is a Neuroinflammation Inhibitor
Nam, Y., Choi, M., Hwang, H., Lee, M., Kwon, B., Lee, W., & Suk, K. (2012) · Phytotherapy Research · doi:10.1002/ptr.4737 · Cited by 45
“Jaceosidin inhibition of microglial neurotoxicity in the microglia/neuron co-culture Neurotoxicity of activated microglia has been previously evaluated using a microglia/neuron co-culture model in a number of reports (Hwang et al., 2008, 2010; Lee et al., 2003; Ock et al., 2010a, 2010b).”
MethodSelf-citation
Behavioral defects induced by chronic social defeat stress are protected by Momordica charantia polysaccharides via attenuation of JNK3/PI3K/AKT neuroinflammatory pathway
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“In animal studies, researchers reported that depressed animals exhibit higher levels of pro-inflammatory cytokines (5) which might inhibit neurotransmission and plasticity, and suppress neurogenesis (6).”
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Curcumin as a putative antidepressant
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Trazodone regulates neurotrophic/growth factors, mitogen-activated protein kinases and lactate release in human primary astrocytes
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Sub-chronic agmatine treatment modulates hippocampal neuroplasticity and cell survival signaling pathways in mice
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MethodSelf-citation
Paroxetine suppresses reactive microglia-mediated but not lipopolysaccharide-induced inflammatory responses in primary astrocytes
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“Previous studies have suggested that regulation of hypothalamic–pituitary–adrenal axis activity 20 or inhibition of immune cell activation 21,22 might contribute to the effects of antidepressants on inflammation, which could be involved in any future study of the mechanism of suppression of C4 by…”
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Imipramine impedes glioma progression by inhibiting YAP as a Hippo pathway independent manner and synergizes with temozolomide
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Suppressive immunoregulatory effects of three antidepressants via inhibition of the nuclear factor-κB activation assessed using primary macrophages of carp ( Cyprinus carpio )
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Mansour, A., Mohamed, B. M. S. A., Aboul‐Fotouh, S., Ibrahim, E. A.-S., Shehata, H., Yassin, N., El‐Eraky, W. I., & Abdel-Tawab, A. M. (2013) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s41020 · Cited by 29
“Additionally, imipramine inhibited the production of TNF-α in whole human blood(61) and microglia and astrocyte cultures.(62) The early reversal of CMS-induced anhedonia by 7-nitroindazole and pentoxifylline in the present work may be explained by their direct inhibition of nNOS and TNF-α.”
Method
Dopaminergic impact of cART and anti-depressants on HIV neuropathogenesis in older adults
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“The TCAs clomipramine and imipramine as well as the SSRI fluoxetine may have antiinflammatory and neuroprotective effects via modulation of glial activation (Hwang, 2008; Obuchowicz, 2014).”
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Repurposing psychiatric medicines to target activated microglia in anxious mild cognitive impairment and early Parkinson's disease.
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BackgroundInfluential
Imipramine enhances cell proliferation and decreases neurodegeneration in the hippocampus after transient global cerebral ischemia in rats
Schiavon, A. P., Milani, H., Romanini, C. V., Foresti, M. L., de Castro, O. W., Garcia‐Cairasco, N., & de Oliveira, R. M. W. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.12.052 · Cited by 26
Inhibition of TNF-α-induced neuronal apoptosis by antidepressants acting through the lysophosphatidic acid receptor LPA1
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What you eat is what you are – A role for polyunsaturated fatty acids in neuroinflammation induced depression?
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Effect of tricyclic antidepressants on L-DOPA-induced dyskinesia and motor improvement in hemi-parkinsonian rats
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Antidepressants, β-Arrestins and GRKs: From Regulation of Signal Desensitization to Intracellular Multifunctional Adaptor Functions
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Retracted: Anti‐inflammatory properties of tianeptine on lipopolysaccharide‐induced changes in microglial cells involve toll‐like receptor‐related pathways
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“Indeed, it has been shown that LPS potentiates the phosphorylation of ERK1/2 and p38 in a dose- and time-dependent manner, leading to increases in iNOS activity and in TNF-a release (Lee et al. 1993; Hwang et al. 2008).”
Background
Retracted
Off-Target Effects of Antidepressants on Vascular Function and Structure
Dimoula, A., Fotellis, D., Aivalioti, E., Delialis, D., Polissidis, A., Patras, R., Kokras, N., & Stamatelopoulos, K. S. (2021) · Biomedicines · doi:10.3390/biomedicines10010056 · Cited by 22
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Background
Celecoxib attenuates depressive-like behavior associated with immunological liver injury in C57BL/6 mice through TNF-α and NF-κb dependent mechanisms
Elnahas, E. M., Zeid, M. S. A., Kawy, H. S. A., Hendawy, N., & Baher, W. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.08.027 · Cited by 20

Authors: Hwang, J., Zheng, L. T., Ock, J., Lee, M. G., Kim, S.-H., Lee, H.-W., Lee, W.-H., Park, H.-C., & Suk, K.
Affiliations: Kyungpook National University (KR)
Korea University Ansan Hospital (KR)
Corresponding author: Suk, Kyoungho
ORCID: Zheng, Long Tai
Ock, Jiyeon
Lee, Maan Gee
Kim, Sang-Hyun
Lee, Ho-Won
Lee, Won-Ha
Park, Hae-Chul
Suk, Kyoungho
Venue: Neuropharmacology
Publisher: Elsevier BV
Published: 2008-10
Volume: 55
Issue: 5
Pages: 826-834
ISSN: 0028-3908 (ISSN-L)
DOI: 10.1016/j.neuropharm.2008.06.045
OpenAlex: W2045253296
Cited by: 181
References: 56
Citations by year: 2026: 4 · 2025: 4 · 2024: 11 · 2023: 8 · 2022: 7 · 2021: 12 · 2020: 10 · 2019: 15 · 2018: 6 · 2017: 10 · 2016: 16 · 2015: 13 · 2014: 12 · 2013: 5 · 2012: 13
FWCI: 7.66
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuropharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: tricyclic antidepressants, clomipramine, imipramine, glial activation, neuroinflammation, neuroprotection, microglia, astrocytes, nitric oxide, inducible nitric oxide synthase, TNF-α, IL-1β, NF-κB, p38 MAPK, lipopolysaccharide, neurodegenerative diseases
MeSH terms: NF-kappaB-Inducing Kinase, Analysis of Variance, Animals, Animals, Newborn, Antidepressive Agents, Tricyclic, Brain, Cell Survival, Cells, Cultured, Clomipramine, Dose-Response Relationship, Drug, Drug Interactions, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Imipramine, Neuroglia, Nitrites, Polysaccharides, Time Factors, Cytokines, Protein Serine-Threonine Kinases, I-kappa B Proteins, p38 Mitogen-Activated Protein Kinases, Mice

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Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants

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