Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: detection with 11C-(R)-PK11195 and small-animal PET.
Intrauterine infection can lead to a fetal inflammatory response syndrome that has been implicated as one of the causes of perinatal brain injury leading to periventricular leukomalacia (PVL) and cerebral palsy. The presence of activated microglial cells has been noted in autopsy specimens of patients with PVL and in models of neonatal hypoxia and ischemia. Activated microglial cells can cause oligodendrocyte damage and white matter injury by release of inflammatory cytokines and production of excitotoxic metabolites. We hypothesized that exposure to endotoxin in utero leads to microglial activation in the fetal brain that can be monitored in vivo by (11)C-(R)-PK11195 (1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide)--a positron-emitting ligand that binds peripheral benzodiazepine receptor sites in activated microglia--using small-animal PET.


METHODS
Pregnant New Zealand White rabbits underwent laparotomy and were injected with 20 and 30 microg/kg of Escherichia coli lipopolysaccharide along the length of the uterus on day 28 of gestation. The pups were born spontaneously at term (31 d) and were scanned using small-animal PET after intravenous administration of (11)C-(R)-PK11195 and by MRI on postnatal day 1. The standard uptake values (SUVs) of the tracer were calculated for the whole brain at 10-min intervals for 60 min after tracer injection. The pups were euthanized after the scan, and brains were fixed, sectioned, and stained for microglial cells using biotinylated tomato lectin.


RESULTS
There was increased brain retention of (11)C-(R)-PK11195--as determined by a significant difference in the slope of the SUV over time--in the endotoxin-treated pups when compared with that of age-matched controls. Immunohistochemical staining showed dose-dependent changes in activated microglia (increased number and morphologic changes) in the periventricular region and hippocampus of the brain of newborn rabbit pups exposed to endotoxin in utero.


CONCLUSIONS
Intrauterine inflammation leads to activation of microglial cells that may be responsible for the development of brain injury and white matter damage in the perinatal period. PET with the tracer (11)C-(R)-PK11195 can be used as a noninvasive, sensitive tool for determining the presence and progress of neuroinflammation due to perinatal insults in newborns.
Kannan
Sujatha
S
Carman and Ann Adams Department of Pediatrics, Wayne State University, Detroit, Michigan 48201, USA. skannan@med.wayne.edu
Saadani-Makki
Fadoua
F
Muzik
Otto
O
Chakraborty
Pulak
P
Mangner
Thomas J
TJ
Janisse
James
J
Romero
Roberto
R
Chugani
Diane C
DC
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology; D002250:Carbon Radioisotopes; D004716:Endometritis / Q000150:complications / Q000276:immunology*; D004731:Endotoxins; D005260:Female; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D017628:Microglia / Q000000981:diagnostic imaging* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology*; D011817:Rabbits; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism
D002250:Carbon Radioisotopes; D004731:Endotoxins; D007546:Isoquinolines; D019275:Radiopharmaceuticals; C044101:endotoxin, Escherichia coli; C037850:PK 11195