Depletion of systemic macrophages by liposome-encapsulated clodronate attenuates increases in brain quinolinic acid during CNS-localized and systemic immune activation.
Quinolinic acid is a neurotoxic tryptophan metabolite produced locally during immune activation. The present study tested the hypothesis that macrophages are an important source. In normal gerbils, the macrophage toxin liposome-encapsulated clodronate depleted blood monocytes and decreased quinolinic acid levels in liver (85%), duodenum (33%), and spleen (51%) but not serum or brain. In a model of CNS inflammation (an intrastriatal injection of 5 microg of lipopolysaccharide), striatal quinolinic acid levels were markedly elevated on day 4 after lipopolysaccharide in conjunction with infiltration with macrophages (lectin stain). Liposome-encapsulated clodronate given 1 day before intrastriatal lipopolysaccharide markedly reduced parenchymal macrophage invasion in response to lipopolysaccharide infusion and attenuated the increases in brain quinolinic acid (by 60%). A systemic injection of lipopolysaccharide (450 microg/kg) increased blood (by 38-fold), lung (34-fold), liver (23-fold), spleen (8-fold), and striatum (25-fold) quinolinic acid concentrations after 1 day. Liposome-encapsulated clodronate given 4 days before systemic lipopolysaccharide significantly attenuated the increases in quinolinic acid levels in blood (by 80%), liver (87%), spleen (80%), and striatum (68%) but had no effect on the increases in quinolinic acid levels in lung. These results are consistent with the hypothesis that macrophages are an important local source of quinolinic acid in brain and systemic tissues during immune activation.
Koennecke
L A
LA
Laboratory of Neurotoxicology, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Zito
M A
MA
Proescholdt
M G
MG
van Rooijen
N
N
Heyes
M P
MP
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects* / Q000276:immunology; D002531:Cerebellum / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004002:Clodronic Acid / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004339:Drug Compounding; D004660:Encephalitis / Q000139:chemically induced; D005260:Female; D005849:Gerbillinae; D037102:Lectins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes; D008264:Macrophages / Q000166:cytology*; D017628:Microglia / Q000166:cytology; D015213:Neuroimmunomodulation / Q000187:drug effects; D037121:Plant Lectins; D017378:Quinolinic Acid / Q000097:blood / Q000134:cerebrospinal fluid*
C045475:Griffonia simplicifolia lectins; D037102:Lectins; D008070:Lipopolysaccharides; D008081:Liposomes; D037121:Plant Lectins; D004002:Clodronic Acid; D017378:Quinolinic Acid