Depletion of systemic macrophages by liposome-encapsulated clodronate attenuates striatal macrophage invasion and neurodegeneration following local endotoxin infusion in gerbils.
CNS-localized inflammation with microglial activation and macrophage infiltration contributes to the pathogenesis of a broad spectrum of neurologic diseases. A direct injection of lipopolysaccharide (LPS) into the striatum of gerbils induced lectin-positive macrophage parenchymal invasion, minimal local microglial staining but extensive neurodegeneration (cresyl violet and silver staining) when evaluated 4 days later. In mice, LPS activated microglia (increased lectin staining of morphologically identified cells) with substantially less macrophage invasion but no neurodegeneration was seen at 4 days post LPS infusion. To evaluate the role of infiltrating macrophages in the neurodegenerative response in gerbils, peripheral macrophages were depleted by an intravenous injection of liposome-encapsulated clodronate. This preparation depleted spleen and liver macrophages (>95%), decreased blood monocytes by 55% and attenuated striatal macrophage infiltration (32 to 73% in five representative sections). Notably, the liposome-encapsulated clodronate reduced the severity of LPS-induced neurodegeneration, as visualized by cresyl violet staining and quantified in 20 serially stained silver sections (total volume, 1.32+/-0.41 mm(3) in liposome-encapsulated clodronate-treated versus 3.04+/-0.72 mm(3) in saline-treated controls). These results indicate that a local LPS infusion in gerbil brain may be a useful model in which to investigate the role of invading macrophages and other inflammatory responses in neurodegeneration in inflammatory neurological disease.
Zito
M A
MA
Laboratory of Neurotoxicology, Building 10, Room 3D42, National Institute of Mental Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Koennecke
L A
LA
McAuliffe
M J
MJ
McNally
B
B
van Rooijen
N
N
Heyes
M P
MP
D000704:Analysis of Variance; D000818:Animals; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004337:Drug Carriers; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity; D005849:Gerbillinae; D007263:Infusions, Parenteral; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D012475:Salmonella
D004337:Drug Carriers; D004731:Endotoxins; D008070:Lipopolysaccharides; D008081:Liposomes; D004002:Clodronic Acid