RT Journal Article
SR Electronic
T1 Microglial Activation in Perinatal Rabbit Brain Induced by Intrauterine Inflammation: Detection with <sup>11</sup>C-(<em>R</em>)-PK11195 and Small-Animal PET
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 946
OP 954
DO 10.2967/jnumed.106.038539
VO 48
IS 6
A1 Kannan, Sujatha
A1 Saadani-Makki, Fadoua
A1 Muzik, Otto
A1 Chakraborty, Pulak
A1 Mangner, Thomas J.
A1 Janisse, James
A1 Romero, Roberto
A1 Chugani, Diane C.
YR 2007
UL http://jnm.snmjournals.org/content/48/6/946.abstract
AB 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 11C-(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 μg/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 11C-(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 11C-(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. Conclusion: 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 11C-(R)-PK11195 can be used as a noninvasive, sensitive tool for determining the presence and progress of neuroinflammation due to perinatal insults in newborns.