Abstract
The positron emission tomography probes 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and 2-tert-butyl-4-chloro-5-{6-[2-(2-[18F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF) are designed to evaluate glycolysis and oxidative phosphorylation, respectively, and are both used to estimate neuronal activity. However, previous studies have shown a discrepancy in these probes’ accumulation in the compromised region, possibly due to the presence of activated microglia acting like deleterious or neuroprotective phenotypes. Hence, we evaluated lipopolysaccharide (LPS)- and interleukin 4 (IL4)-stimulated microglial uptake of [14C]2DG and [18F]BCPP-EF to give a new insight into the hypothesis that different uptake of [18F]FDG and [18F]BCPP-EF can be ascribed to the different metabolic pathways activated during microglial activation. LPS or IL4 stimulation increased the proinflammatory or anti-inflammatory marker gene expression in microglial cells. In LPS-stimulated cells, [14C]2DG uptake and glycolysis related gene expression were elevated, and [18F]BCPP-EF uptake was reduced. In IL4-stimulated cells, [18F]BCPP-EF uptake was increased, and [14C]2DG uptake was decreased. The expression of genes involved in glycolysis and mitochondrial complex I subunits was not changed by IL4 stimulation. The uptake of [14C]2DG and [18F]BCPP-EF differs in LPS- and IL4-stimulated polarized microglial cells. The present results suggest that the in vivo accumulation of metabolic tracers [18F]FDG and [18F]BCPP-EF can be influenced by the different aspects of neuroinflammation.
Highlights
Brain positron emission tomography (PET) is a powerful tool for elucidating the pathophysiology of neurodegenerative diseases in vivo[1,2] to allow differential diagnosis of these d iseases[3,4]
The time course of proinflammatory and anti-inflammatory effects of microglia has been reported to be different following acute brain injury[18], and the energy metabolism pathway activity is shown to change according to microglial activation states as follows: the glucose consumption rate is increased in LPS and interferon γ (INFγ)-stimulated microglia and decreased in interleukin 4 (IL4) stimulated microglia[19], while the oxygen consumption rate (OCR), an oxidative phosphorylation (OXPHOS) index, is decreased in IFNγ- and LPS + IFNγ-stimulated microglia and increased in IL4-stimulated microglia[20,21]
Arginase 1 (Arg1) expression levels were significantly increased at 6 h (262 ± sevenfold in BV-2 cells, p < 0.01; 54.1 ± 7.8-fold in MG5 cells, p < 0.01) and at later time points in IL4-stimulated cells compared with control cells (Fig. 1G,H)
Summary
Brain positron emission tomography (PET) is a powerful tool for elucidating the pathophysiology of neurodegenerative diseases in vivo[1,2] to allow differential diagnosis of these d iseases[3,4]. A reduction in [18F]FDG accumulation is observed in the atrophic region in the brains of elderly individuals[7] and in the precuneus/posterior cingulate, lateral parietal and frontal cortices in patients with Alzheimer’s disease (AD)[8] in parallel with the progression of AD pathology[9]. This suggests that reduced [18F]FDG accumulation relates to neural hypoactivity and/or neuronal loss. To specify the cellular accumulation of radiotracers in such microglia independently of neuron and the other glial cells, we used chemically-induced activated microglia in an in vitro experimental setting instead of in vivo settings where neuron and glial cells coexist
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