Neuroinflammation in Murine Endotoxemia: A Dual‐Tracer MicroPET Evaluation

Abstract

In sepsis and other disorders characterized by peripheral immune and metabolic dysregulation, the brain also is affected and brain dysfunction, including neuroinflammation, metabolic changes and cognitive impairment have been reported (Annu Rev Immunol, 2018, 36:783-812). Non-invasive evaluation of neuroinflammation is important for strategizing new diagnostic and therapeutic approaches targeting the brain. Here we utilized Micro Positron Emission Tomography (microPET) with [18F]Fluoro-2-deoxy-2-D-glucose (18FDG) and 11C-Peripheral Benzodiazepine Receptor ([11C]PBR) to evaluate brain metabolic alterations and microglia activation (indicating neuroinflammation) during murine endotoxemia. Lipopolysaccharide (LPS, endotoxin) (2 mg/kg) or saline was injected (i.p.) in male C57Bl/6 mice 6 hrs prior to microPET imaging. [11C] PBR28 (~0.5 mCi) was injected via the tail vein followed by 60 mins dynamic imaging. Subsequently, 18FDG (0.5 mCi) was injected i.p. with a 10 mins static scan acquired following 40 mins uptake. Brain images were analyzed in a standard anatomical space using Statistical Parametric Mapping. Significantly (P<0.01) increased glucose metabolism in endotoxemic mice (vs controls) was observed in the hippocampal CA2/CA3 region and other brain areas. Increased [11C]PBR28 binding (P<0.05) was also determined in the hippocampal CA2/CA3 region. These brain alterations were associated with significantly increased serum cytokine levels (TNF, IL-6, IL-1β, and IL-10) at 6 hrs following administration of the same (2mg/kg, i.p.) endotoxin dose. These results indicate brain hypermetabolic activity and neuroinflammation during endotoxemia specifically affecting the hippocampus – an area with a primary role in memory and cognition. These findings support further development of PET-based evaluation of neuroinflammation in preclinical and clinical settings of inflammatory and metabolic disorders.