Multiparametric MRI assessment of acute neuroinflammation in a murine model of peripheral LPS stimulation

Neuroinflammation is implicated in the pathogenesis of several central nervous system disorders. Excessive and prolonged neuroinflammation impacts disease progression and potential interventions. A widely used model of peripherally-induced neuroinflammation involves the intraperitoneal administration of the endotoxin lipopolysaccharide (LPS) to mice. In this exploratory study, magnetic resonance imaging (MRI) was used to non-invasively investigate in the brain acute neuroinflammation induced by peripheral LPS stimulation and in combination with the microglia depleting effects of the colony stimulating factor 1 receptor kinase inhibitor BLZ945.

Multiparametric MRI, including T₂-weighted signal, magnetization transfer ratio MTR, and apparent diffusion coefficient ADC, was applied to analyze the model. LPS was administered intraperitoneally once daily from day 1 to day 4 at a dose of 0.5 mg/kg. Post-mortem analyses comprised cytokine/chemokine measurements in the blood and brain, immunohistochemistry of microglia and astrocytes, and brain autoradiography using the TSPO radiotracer [³H]PK11195. BLZ945 (200 mg/kg p.o. daily) was given from day - 7 to day 4.

On day 4 of LPS administration, T₂-weighted signal and MTR increased, while ADC decreased in several brain regions. Neuroinflammation was confirmed by immunohistochemistry, which revealed an increase of microglia and astrocytes in the cortex. Additionally, autoradiography showed increased uptake of [³H]PK11195 in the cortex and thalamus/midbrain of animals receiving LPS. Treatment with BLZ945 resulted in a reduction of the LPS-elicited response, as revealed in vivo by MRI and confirmed by post-mortem histology and autoradiography analysis.

The present findings highlight the potential of non-contrast-enhanced MRI to assess acute neuroinflammation-related changes in several mouse brain areas upon peripheral LPS stimulation. The assessment of multiple parameters provided sufficient sensitivity to detect pharmacological modulation of the neuroinflammatory response elicited by the endotoxin.