Imaging of microglial activation in experimental bacterial meningitis using PET/CT
Vijayasree.V. Giridharan1, Giselli Scaini1, Jaqueline S Generoso2, Lutiana R Simoes2, Diogo Dominguini2, Selvaraj Sudhakar1, Felipe Dal-Pizzol2, Joao Quevedo1, Tatiana Barichello1*
1The University of Texas Health Science Center at Houston, TX, USA
2University of Southern Santa Catarina, Criciúma, SC, Brazil.
Background: Bacterial meningitis is the most devastating CNS infection with acute and long-term neurological consequences. Microglia endowed with a vast repertoire mechanism activated during meningitis. The activated microglia express robust increase of translocator protein (TSPO) which can be measured in vivo with [11C]PBR28 radiotracer using Positron emission tomography and computed tomography (PET/CT). We hypothesize that the persistent activation of microglia during meningitis contributes to aftermath long-term cognitive impairment.
Methods: In this context, Male Wistar rats were induced meningitis by Streptococcus pneumoniae through cisterna magna and treated with ceftriaxone. In acute and chronic model, rats were imaged with PET/CT using [11C]PBR28 at 24 h and 10 days after meningitis induction respectively. Following imaging, the expression of TSPO, cardiolipin, cytokines, microglia, and apoptosis markers in prefrontal cortex and hippocampus were evaluated. Before imaging, rats from chronic model subjected to behavioral test such as open field, step-down inhibitory avoidance and novel object recognition task.
Results: The survivors from acute model demonstrated increased uptake of [11C]PBR28 -microglia activation in PET imaging with simultaneous increase in TSPO expression as compared to control group. There was increased expression of IL-1α, IL-1β, IL-6, IL-18, IFN-γ, TNF-α, Iba-1, GFAP and caspase-3. In chronic survivors, we observed increased uptake of [11C]PBR28-microglia activation with simultaneous increase in TSPO expression and decrease in cardiolipin levels. The expression of TNF-α, Iba-1, GFAP, caspase-3 and caspase-9 was increased in hippocampus. Persistent microglial action in hippocampus explains the memory impairment observed in different behavioral task from chronic survivors.
Conclusion: Thus, TSPO-PET could potentially be used as an imaging biomarker of diffuse neuro-inflammation in bacterial meningitis and further translational approach could help to identify patients who will soon enter the progressive long-term cognitive impairment.