Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide.
Circumstantial evidence has suggested that activated microglia may be associated with the pathogenesis of depression. Pro-inflammatory cytokines may also be involved. Therefore, we examined the effects of various types of antidepressants, as well as the mood-stabilizer lithium chloride, on interferon-gamma (IFN-gamma)-induced microglial production of the pro-inflammatory mediators interleukin-6 (IL-6) and nitric oxide (NO). Treatment of the murine microglial 6-3 cells with 100 U/ml of IFN-gamma resulted in an eightfold increase in IL-6 and a tenfold increase in NO into the culture medium. Pretreatment with the selective serotonin reuptake inhibitor fluvoxamine, the relatively selective noradrenaline reuptake inhibitor reboxetine, or the non-selective monoaminergic reuptake inhibitor imipramine, significantly inhibited IL-6 and NO production in a dose-dependent manner. These inhibitions were reversed significantly by SQ 22536, a cyclic adenosine monophosphate (cAMP) inhibitor, and, except for reboxetine, by the protein kinase A (PKA) inhibitor Rp-adenosine3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-3',5'-cAMPS). Lithium chloride, which is believed to act by inhibiting the calcium-dependent release of noradrenaline, had a different spectrum of action on microglial 6-3 cells. It enhanced IFN-gamma-stimulated IL-6 production and inhibited NO production. The inhibitory effect of lithium chloride was not reversed by either SQ 22536 or Rp-3',5'-cAMPS. These results suggest that antidepressants have inhibitory effects on IFN-gamma-activated microglia and these effects are, at least partially, mediated by the cAMP-dependent PKA pathway. On the other hand, the mood stabilizer and anti-manic agent lithium chloride has mixed effects on IFN-gamma-induced microglial activation.
Hashioka
Sadayuki
S
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582 Japan. hashioka@interchange.ubc.ca
Klegeris
Andis
A
Monji
Akira
A
Kato
Takahiro
T
Sawada
Makoto
M
McGeer
Patrick L
PL
Kanba
Shigenobu
S
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D018692:Antimanic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology; D002460:Cell Line; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009569:Nitric Oxide / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000928:Antidepressive Agents; D018692:Antimanic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D014179:Neurotransmitter Uptake Inhibitors; D009569:Nitric Oxide; D007371:Interferon-gamma; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D018021:Lithium Chloride