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Microglial Activation in Perinatal Rabbit Brain Induced by Intrauterine Inflammation: Detection with ¹¹C-(R)-PK11195 and Small-Animal PET

¹ Carman and Ann Adams Department of Pediatrics, Wayne State University, Detroit, Michigan; ² Department of Radiology, Wayne State University School of Medicine, Detroit, Michigan; ³ Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan; ⁴ Perinatology Research Branch, NICHD, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland and Detroit, Michigan; and ⁵ Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan

Correspondence: For correspondence or reprints contact: Sujatha Kannan, MD, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201. E-mail: skannan{at}med.wayne.edu

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.

Key Words: perinatal brain injury • intrauterine inflammation • small-animal PET • ¹¹C-(R)-PK11195 • microglia

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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				F. Saadani-Makki, S. Kannan, M. Makki, O. Muzik, J. Janisse, R. Romero, and D. Chugani Intrauterine Endotoxin Administration Leads to White Matter Diffusivity Changes in Newborn Rabbits J Child Neurol, September 1, 2009; 24(9): 1179 - 1189. [Abstract] [PDF]

				S. Kannan, B. Balakrishnan, O. Muzik, R. Romero, and D. Chugani Positron Emission Tomography Imaging of Neuroinflammation J Child Neurol, September 1, 2009; 24(9): 1190 - 1199. [Abstract] [PDF]