In-vivo imaging of microglial activation using a peripheral benzodiazepine receptor ligand, C-11-CB148 and animal-pet folliwing ethanol injury in rat striatum

Fumitaka Ito, Gen Kudo, Hiroshi Toyama, Kentaro Hatano, Hiromi Suzuki, Masanori Ichise, Hiroshi Yamaguchi, Katsuhiko Sekimata, Takashi Kato, Kazuhiro Katada, Mariana Serra, Giuseppe Trapani, Makoto Sawada, Kengo Ito

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Abstract

Background and aims: Microglia plays an active part in brain injury and degeneration. The transition of microglia from the normal resting state to the activated state is associated with an increased expression of peripheral benzodiazepine receptors (PBRs). Increased PBRs may be used as a marker for detecting activated microglia in vivo. PET imaging of microglial activation using [C-11]-PK11195(PK), a PBRs ligand, has been investigated in several neurological conditions. Based on our basic mice experiments,a new PBR ligand, [C-11]-CB148(CB), has higher affinity than does PK. We investigated if CB PET can show activated microglia in a rat brain injury model. Methods: On day 1, under pentobarbital anesthesia, 8 μl ethanol was injected into the rat right striatum through Hamilton syringe using a steotaxic operative procedure. On day 3, MRI scans were performed to evaluate brain morphologically. On day 4, dynamic PET scans were performed for 64 min with an animal PET scanner (SHR-2000 animal PET scanner, Hamamatsu Photonics) under chloral hydrate anesthesia after a bolus injection of 39-64 MBq of CB through tail vein. Nine ethanol-injured rats and 7 non-injured control rats were evaluated. To avoid arterial sampling, we evaluated the PBRs binding with a method to estimate normalized PBRs distribution volume (V*) with 'reference' tissue containing PBRs by Ichise (Neroimage2004;22 supple2:T149-50). V* was defined as the distribution volume (V) normalized by the 'reference' region tracer delivery (K1′). V*= V/ K1′= R1/ k2 and R1= K1/ K1′ were estimated voxel-wise with two tissue parameter multilinear reference tissue model by Ichise(JCBFM2003;23:1096-112). On the coronal PET image, regions of interest (ROI) were placed on bilateral striatum (ST) guided by a rat stereotaxic atlas and Harderian glands ('reference' region). The animals were euthanized after the PET scanning and immunohistochemical staining was performed for confirmation of the presence of activated microglia. Densities of activated microglia in each rat striatum were measured. Results: The PBRs V* values (min) in injured right ST were significantly higher by 12% than in non-injured left ST (14.82±3.63vs.12.67±6.24, p<0.05). Similarly, the PBR V* right/left striatum ratios were significantly higher by 11% than in control rats (1.1±1.3 vs.1.0±0.1, p<0.05).On immunohistochemical staining, IB4-lection positive cells showing activated microglia were shown around the ethanol injected tract in the right striatum but not in the non-injured left striatum. V* values (min) correlated highly with densities of activated microglia (y=0.0019x ? 0.263, R2=0.79, P=0.0002). Conclusion: These Results: suggest that CB PET imaging and V* analysis would be a useful tool to evaluate microglial activation(brain inflammation) in rat brain.

Original languageEnglish
Pages (from-to)PP08-04U
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue numberSUPPL. 1
Publication statusPublished - 13-11-2007

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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    Ito, F., Kudo, G., Toyama, H., Hatano, K., Suzuki, H., Ichise, M., Yamaguchi, H., Sekimata, K., Kato, T., Katada, K., Serra, M., Trapani, G., Sawada, M., & Ito, K. (2007). In-vivo imaging of microglial activation using a peripheral benzodiazepine receptor ligand, C-11-CB148 and animal-pet folliwing ethanol injury in rat striatum. Journal of Cerebral Blood Flow and Metabolism, 27(SUPPL. 1), PP08-04U.