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An In Vivo Study of a Rat Fluid-Percussion-Induced Traumatic Brain Injury Model with [11C]PBR28 and [18F]flumazenil PET Imaging

2021.01.19.

Krishna Kanta Ghosh et al., International Journal of Molecular Sciences, 2021

Summary

Traumatic brain injury (TBI) modelled by lateral fluid percussion-induction (LFPI) in rats is a widely used experimental rodent model to explore and understand the underlying cellular and molecular alterations in the brain caused by TBI in humans. The present study aims to investigate whether the two adioligands, 11C-PBR28 and 18F-flumazenil, are able to accurately quantify in vivo molecular-cellular changes in a rodent TBI-model for two different biochemical targets of the processes. As 11C-PBR28 is a radioligand of the 18 kD translocator protein (TSPO), the up-regulation of which is coupled to the level of neuroinflammation in the brain, and 18F-flumazenil is a radioligand for GABAA-benzodiazepine receptors, whose level capable of indicating at a high precision the neuronal loss that ensues in various brain disorders and injuries, the use of the two radioligands may reveal two critical features of TBI. An up-regulation in the 11C-PBR28 uptake triggered by the LFP in the injured (right) hemisphere was noted on day 14, while the uptake of 18F-flumazenil was down-regulated on day 14. When comparing the left (contralateral) and right (LFPI) hemispheres, the differences between the two in neuroinflammation were obvious. In vitro immunohistochemical analyses on the corpus callosum and hippocampal sections of the cerebrum were done to validate the results obtained in the PET imaging Results demonstrate a potential way to measure the molecular alterations in a rodent-based TBI model using PET imaging with 11C-PBR28 and 18F-flumazenil. These radioligands are promising options that can be eventually used in exploring the complex in vivo pharmacokinetics and delivery mechanisms of nanoparticles in TBI treatment.

Results from nanoScan PET/MRI

According to a standard LFP procedure, a combination of focal and diffuse injury was inflicted on the cerebral cortex and hippocampus of the right hemisphere of rats to create a TBI model for the study. The left hemisphere served as an internal control for the study. Following the LFP procedure on the brain’s right hemisphere of 12 Sprague Dawley rats, day 2 post operation 3D dynamic PET scans were performed using the nanoScan PET/MRI scanner. After injecting approximately 30±4MBq 11C-PBR28 or 18±4MBq 18F-flumazenil to the tail vein, dynamic 63min PET scan was performed with 11C-PBR28. The second PET radioligand 18F-flumazenil was injected 80min later, and the animals were scanned for a duration of 90min. The detailed time frames for the respective scan protocols were as follows: 8x15s, 4x30s, 2x1min, 2x2min, 4x5min, 3x10min for 11C-PBR28; 8x15s, 4x30s, 2x1min, 2x2min, 4x5min and 6x10min for 18F-flumazenil.

Results show:

  • Compared to day 2 post-op, there is an increase in the uptake of 11C-PBR28 on day 14 due to the LFP in the right hemisphere (injured)
  • 18F-flumazenil uptake was down-regulated on day 14, compared to day 2
  • The time activity curves (TACs) of the whole brain also clearly demonstrate that there was a higher 11C-PBR28 and lower 18F-flumazenil uptake in day 14 as compared to day 2

  • When juxtaposing the right and left hemispheres using an area-under-the-curve (AUC) measure, the discrepancies between the two hemispheres for the 11C-PBR28 radiotracer were apparent. This is an indication that local increases in neuroinflammation due to the physical impact can be observed in the LFPI TBI rodent model. On the other hand, while 18F-flumazenil uptake is slightly higher in the left hemisphere, the lack of marked changes between the two hemispheres may reflect either the lack of neuron density alterations or the inappropriateness of the radioligand in indicating neuron density changes. This is the first LFPI TBI rat study to evaluate neuroinflammation and loss of neuronal density using two radioligands subsequently on the same day.

Full article on mdpi.com

 

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