Translocator protein (18 kDa)/peripheral benzodiazepine receptor specific ligands induce microglia functions consistent with an activated state.
In the brain, translocator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor (PBR), is a glial protein that has been extensively used as a biomarker of brain injury and inflammation. However, the functional role of TSPO in glial cells is not well characterized. In this study, we show that the TSPO-specific ligands R-PK11195 (PK) and Ro5-4864 (Ro) increased microglia proliferation and phagocytosis with no effect on migration. Both ligands increased reactive oxygen species (ROS) production, and this effect may be mediated by NADPH-oxidase. PK and Ro also produced a small but detectable increase in IL-1β release. We also examined the effect of PK and Ro on the expression of proinflammatory genes and cytokine release in lipopolysaccharide (LPS) and adenosine triphosphate (ATP) activated microglia. PK or Ro had no effect on LPS-induced increase of pro-inflammatory genes, but they both decreased the ATP-induced increase of COX-2 gene expression. Ro, but not PK, enhanced the LPS-induced release of IL-1β. However, Ro decreased the ATP-induced release of IL-1β and TNF-α, and PK decreased the ATP-induced release of TNF-α. Exposure to Ro in the presence of LPS increased the number of apoptotic microglia, an effect that could be blocked by PK. These findings show that TSPO ligands modulate cellular functions consistent with microglia activation. Further, when microglia are activated, these ligands may have therapeutic potential by reducing the expression of pro-inflammatory genes and cytokine release. Finally, Ro-like ligands may be involved in the elimination of activated microglia via apoptosis.
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Judy
J
Choi
Masataka
M
Ifuku
Mami
M
Noda
Tomás R
TR
Guilarte
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001570:Benzodiazepinones / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*
D001570:Benzodiazepinones; D016207:Cytokines; D000960:Hypolipidemic Agents; D007546:Isoquinolines; D008024:Ligands; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D000255:Adenosine Triphosphate; D001973:Bromodeoxyuridine; C037850:PK 11195