Inhibitory effects of SSRIs on IFN-γ induced microglial activation through the regulation of intracellular calcium.
Microglia, which are a major glial component of the central nervous system (CNS), have recently been suggested to mediate neuroinflammation through the release of pro-inflammatory cytokines and nitric oxide (NO). Microglia are also known to play a critical role as resident immunocompetent and phagocytic cells in the CNS. Immunological dysfunction has recently been demonstrated to be associated with the pathophysiology of depression. However, to date there have only been a few studies on the relationship between microglia and depression. We therefore investigated if antidepressants can inhibit microglial activation in vitro. Our results showed that the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline significantly inhibited the generation of NO and tumor necrosis factor (TNF)-α from interferon (IFN)-γ-activated 6-3 microglia. We further investigated the intracellular signaling mechanism underlying NO and TNF-α release from IFN-γ-activated 6-3 microglia. Our results suggest that paroxetine and sertraline may inhibit microglial activation through inhibition of IFN-γ-induced elevation of intracellular Ca(2+). Our results suggest that the inhibitory effect of paroxetine and sertraline on microglial activation may not be a prerequisite for antidepressant function, but an additional beneficial effect.
Horikawa
Hideki
H
Department of Neuropsychiatry, Graduate School of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka City, Fukuoka 812-8582, Japan.
Kato
Takahiro A
TA
Mizoguchi
Yoshito
Y
Monji
Akira
A
Seki
Yoshihiro
Y
Ohkuri
Takatoshi
T
Gotoh
Leo
L
Yonaha
Megumi
M
Ueda
Tadashi
T
Hashioka
Sadayuki
S
Kanba
Shigenobu
S
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000928:Antidepressive Agents; D002118:Calcium; D016898:Interferon-alpha; D007371:Interferon-gamma; D015847:Interleukin-4; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors