Trajectory of neuro-inflammation and microglial activation assessed using Translocator protein (18kDa TSPO) and positron emission tomography (PET) imaging in bacterial meningitis

Abstract

Abstract Here we present novel data from acute (24 hours) and chronic (10 days) pneumococcal meningitis rat survivors evaluating microglia activation through [11C] PBR28, a tracer targeting the TSPO using PET-imaging. Wistar rats received an injection of Streptococcus pneumoniae or artificial-CSF through the cisterna magna following by ceftriaxone/100 mg/kg/7days. At 24 hours and 10 days the animals were subjected to TSPO-PET-imaging. Following the imaging IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-17, IL-18, IFN-γ, TNF-α, and microglial marker Iba-1 and astrocyte marker GFAP were evaluated in prefrontal cortex and hippocampus (n = 7). In chronic phase, the animals were subjected to open field, step-down inhibitory avoidance and in novel object recognition task, n = 10. In acute phase, the imaging results revealed that in amygdala, cortex, hippocampus, hypothalamus, midbrain, and thalamus (p < 0.05) uptake of [11C] PBR28 was greater in the meningitis group as compared to the control group. We observed increased expression of pro-inflammatory markers such as IL-1α, IL-1β, IL-6, IL-18, IFN-γ, TNF-α, Iba-1, and GFAP expression at 24 h (p < 0.05). In the chronic phase, in amygdala, hippocampus, and thalamus (p < 0.05) uptake of [11C] PBR28 was greater in the meningitis group. The control group presented retention of habituation memory, aversive memory and long-term recognition memory. However, animals in the meningitis group demonstrated memory impairment in all behavioral tasks. TNF-α, Iba-1, and GFAP expression increased in chronic phase survivors (p < 0.05). The above results support our hypothesis that increased activation of brain microglia is associated with behavioral changes in experimental model of meningitis.