Multiparametric assessment of acute and subacute ischemic neuronal damage: A small animal positron emission tomography study with rat photochemically induced thrombosis model

Abstract

We evaluated sequential changes in rat brain function up to 14 days after focal ischemic insult with a small animal positron emission tomography (PET). Unilateral focal ischemic cerebral damage was induced by left middle cerebral artery occlusion with a photochemically induced thrombosis (PIT) method. PET scans were conducted with [(11)C](R)-PK11195 ([(11)C](R)-PK) for peripheral benzodiazepine receptor (PBR), [(11)C]flumazenil ([(11)C]FMZ) for central benzodiazepine receptor (CBR), and [(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) for glucose metabolism at before (as "Normal") and after PIT. At 1 and 3 days after PIT, [(18)F]FDG indicated lower uptake in the infarct area. Interestingly, unexpectedly high-[(18)F]FDG uptake was observed in the peri-infarct area surrounding the infarct area at day 7. The high-[(18)F]FDG uptake region completely overlapped with the high-[(11)C](R)-PK uptake region at day 7, which resulted in the underestimation of neuronal damage. Immunohistochemical data also suggested that the high-[(18)F]FDG uptake peak at day 7 was caused by inflammation including microglial cell activation. In contrast, imaging with [(11)C]FMZ indicated cortical neuronal damage on days 7 and 14 without any disturbance by microglial formation. These results indicated that [(18)F]FDG might not be a suitable ligand for ischemic neuronal damage detection from acute to subacute phases.

PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

“…Some reports showed the increase in 11 C-PK-11195 binding in peri-infarct regions, but not in infarct region, at Day-7 in rat ischemic model. 9,10 Another report reported no significant changes in 11 C-PK-11195 binding in either peri-infarct or infarct regions at Day-9, similarly increase in both regions Day-21 and later in baboon ischemic model, while 11 C-FMZ binding was significantly reduced from Day-2 and later. 29 Take together, the relationship between neuronal damage and inflammation might be altered depending on the species, models and timing after ischemic insult.…”

“…39 We recently reported a relatively slow temporal change in the rat brain uptake of 11 C-FMZ after focal cerebral ischemia after Imaging impaired MC-I in ischemic monkey brain H Tsukada et al photochemically induced thrombosis. 9 In addition, 3 H-FMZ binding in vivo was relatively insensitive to cell death induced by sodium nitroprusside, a traditional NO donor compound. 40 These three previous studies and the present data suggest that FMZ binding to CBR might be considerably more stable against cell death, and providing more time to detect neuronal damage in the brain.…”

“…It was suggesting that 18 F-BCPP-EF could be useful to detect ischemic neuronal damage at the subacute phase 7 days after ischemic insult (Day-7), 7 at which time unexpectedly higher 18 F-fluoro-2-deoxy-Dglucose (FDG) uptake was observed in the damaged area than in the contralateral intact area. 9,10 The FDG-PET is a well-established technique for quantitative imaging of the regional cerebral metabolic rate of glucose (rCMRglc) in living brain, which is based on the assumption that rCMRglc reflects energy metabolism via oxidative phosphorylation. However, the unexpectedly high uptake of 18 F-FDG in ischemia-damaged areas suggested that 18 F-FDG was taken up into not only normal tissues but also inflammatory regions with microglial activation.…”

“…However, the unexpectedly high uptake of 18 F-FDG in ischemia-damaged areas suggested that 18 F-FDG was taken up into not only normal tissues but also inflammatory regions with microglial activation. 9,10 Since recent PET research has indicated that neurodegenerative disorders showed neuroinflammation with microglial activation, 11 PET probes to image MC-I activity would be favorable for more accurate assessment of neurodegenerative damage using PET.…”

Novel PET Probes18F-BCPP-EF and18F-BCPP-BF for Mitochondrial Complex I: A PET Study in Comparison with18F-BMS-747158-02 in Rat Brain

“…However, this technique measures only the first part of glucose metabolism in the phosphorylation of glucose to glucose-6-phosphate by hexokinase (EC 2.7.1.1). Therefore, 18 F-FDG is taken up into not only normal tissues but also inflammatory regions observed in the subacute phase after transient focal ischemia in rodent models (11,12). Because recent reports indicated that several neurodegenerative disorders-schizophrenia, major depression, dementia (13,14), and autism (15)-induced neuroinflammation, 18 F-FDG may lead to underestimation of the neurodegenerative damage in these diseases.…”