Assessing long-term neuroinflammatory responses to encephalopathy using MRI approaches in a rat endotoxemia model

Abstract

Sepsis-associated encephalopathy (SAE) induces neuroinflammation, which is associated with cognitive impairment (CI). CI is also correlated with aging. We used contrast-enhanced magnetic resonance imaging (MRI), perfusion MRI, and MR spectroscopy to assess long-term alterations in BBB permeability, microvascularity, and metabolism, respectively, in a rat lipopolysaccharide-induced SAE model. Free radical-targeted molecular MRI was used to detect brain radical levels at 24 h and 1 week post-LPS injection. CE-MRI showed increased Gd-DTPA uptake in LPS rat brains at 24 h in cerebral cortex, hippocampus, thalamus, and perirhinal cortex regions. Increased MRI signal intensities were observed in LPS rat brains in cerebral cortex, perirhinal cortex, and hippocampus regions 1 week post-LPS. Long-term BBB dysfunction was detected in the cerebral cortex at 6 weeks post-LPS. Increased relative cerebral blood flow (rCBF) in cortex and thalamus regions at 24 h, decreased cortical and hippocampal rCBF at 6 weeks, decreased cortical rCBF at 3 and 12 weeks, and increased thalamus rCBF at 6 weeks post-LPS, were detected. MRS indicated that LPS-exposed rat brains had decreased: NAA/Cho metabolite ratios at 1, 3, 6, and 12 weeks; Cr/Cho at 1, 3, and 12 weeks; and Myo-Ins/Cho at 1, 3, and 6 weeks post-LPS. Free radical imaging detected increased radical levels in LPS rat brains at 24 h and 1 week post-LPS. LPS-exposed rats were compared to saline-treated controls. We clearly demonstrated BBB dysfunction, impaired vascularity, and decreased brain metabolites, as measures of long-term neuroinflammatory indicators, as well as increased free radicals in a LPS-induced rat SAE model.

Review—Quantification of Hydrogen Peroxide by Electrochemical Methods and Electron Spin Resonance Spectroscopy

“…Up to now, IST has been applied in a variety of in-vitro and in-vivo studies, including animal disease models, in order to elucidate the impact of radical formation under physiological and pathological conditions. 451,464,[470][471][472] Instrumentation for ESR spectroscopy.-ESR spectrometers used in research and in clinical applications are rather expensive and complex instruments requiring experienced personnel for operation and evaluation of experiments. Currently, high-performance and automatized desktop ESR spectrometers become available, which can be operated following validated protocols for monitoring radicals in systems of living cells.…”

Analysis of retention of gadolinium by brain, bone, and blood following linear gadolinium‐based contrast agent administration in rats with experimental sepsis

“…Our group has previously characterized an experimental LPS endotoxemia‐induced rat model of sepsis as resulting in secondary neuroinflammation and, based on evidence for delayed parenchymal enhancement on contrast‐enhanced MRI, of associated BBB disruption . Using this LPS‐induced model, we herein report greater deposition of Gd in the brain in LPS‐treated rats than in control animals throughout the interval of observation (to 6 weeks following GBCA administration).…”

“…It is possible that some degree of acute renal injury in the LPS‐treated rats during the first 24 hours after contrast injection could have resulted in higher GBCA levels in the blood and delivery to the brain, which may have normalized by 24 hours. Additionally, we have reported that brain perfusion is increased during the first 24 hours in LPS‐treated rats, which could also result in increased delivery of GBCA to the brain . Regardless of the specific and possibly multifactorial mechanism of increased Gd deposition in the brains of LPS‐treated rats, substantial deposition of Gd also occurs even in control rats for sustained intervals following injection of linear GBCA.…”

“…Additionally, we have reported that brain perfusion is increased during the first 24 hours in LPS-treated rats, which could also result in increased delivery of GBCA to the brain. 23 Regardless of the specific and possibly multifactorial mechanism of increased Gd deposition in the brains of LPS-treated rats, substantial deposition of Gd also occurs even in control rats for sustained intervals following injection of linear GBCA.…”

“…At 24 hours following GBCA injection, the blood content of Gd in LPS‐treated rats was approximately 44.7% higher than in control rats, although this difference was not significant. We have shown that a single high dose of LPS to rats results in multiple effects seen in septic patients, including pulmonary and neuroinflammation . It is possible that some degree of acute renal injury in the LPS‐treated rats during the first 24 hours after contrast injection could have resulted in higher GBCA levels in the blood and delivery to the brain, which may have normalized by 24 hours.…”