Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants.
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.
Hwang
Jaegyu
J
Department of Pharmacology, School of Medicine, Brain Science and Engineering Institute, Kyungpook National University, Joong-gu, Daegu 700-422, Republic of Korea.
Zheng
Long Tai
LT
Ock
Jiyeon
J
Lee
Maan Gee
MG
Kim
Sang-Hyun
SH
Lee
Ho-Won
HW
Lee
Won-Ha
WH
Park
Hae-Chul
HC
Suk
Kyoungho
K
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002997:Clomipramine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D051379:Mice; D009457:Neuroglia / Q000187:drug effects*; D009573:Nitrites / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D000929:Antidepressive Agents, Tricyclic; D002997:Clomipramine; D016207:Cytokines; D020672:I-kappa B Proteins; D007099:Imipramine; D009573:Nitrites; D011134:Polysaccharides; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase