Son E, et al. Korean J Physiol Pharmacol. 2020 Mar;24(2):173-183. https://doi.org/10.4196/kjpp.2020.24.2.173

This study quantitatively measured the changes in metabolites in the hippocampal lesions of a rat model of cuprizone-induced demyelination as detected using in vivo 7 T proton magnetic resonance spectroscopy. Nineteen Sprague Dawley rats were randomly divided into two groups and fed a normal chow diet or cuprizone (0.2%, w/w) for 7 weeks. Demyelinated hippocampal lesions were quantitatively measured using a 7 T magnetic resonance imaging scanner. All proton spectra were quantified for metabolite concentrations and relative ratios. Compared to those in the controls, the cuprizone-induced rats had significantly higher concentrations of glutamate (p = 0.001), gamma-aminobutyric acid (p = 0.019), and glutamate + glutamine (p = 0.001); however, creatine + phosphocreatine (p = 0.006) and myo-inositol (p = 0.001) concentrations were lower. In addition, we found that the glutamine and glutamate complex/total creatine (p < 0.001), glutamate/total creatine (p < 0.001), and GABA/total creatine (p = 0.002) ratios were significantly higher in cuprizone-treated rats than in control rats. Our results showed that cuprizone-induced neuronal demyelination may influence the severe abnormal metabolism in hippocampal lesions, and these responses could be caused by microglial activation, mitochondrial dysfunction, and astrocytic necrosis.

Aryl hydrocarbon receptor (AhR) antagonism can mitigate cellular damage associated with cerebral ischaemia and reperfusion (I/R) injury. This study investigated the neuroprotective effects of AhR antagonist administration before reperfusion in a rat stroke model and influence of the timing of AhR antagonist administration on its neuroprotective effects. Magnetic resonance imaging (MRI) was performed at baseline, immediately after, and 3, 8, and 24 h after ischaemia in the sham, control (I/R injury), TMF10 (trimethoxyflavone [TMF] administered 10 min post-ischaemia), and TMF50 (TMF administered 50 min post-ischaemia) groups. The TMF treatment groups had significantly fewer infarcts than the control group. At 24 h, the relative apparent diffusion coefficient values of the ischaemic core and peri-infarct region were significantly higher and relative T2 values were significantly lower in the TMF10 groups than in the control group. The TMF treatment groups showed significantly fewer terminal deoxynucleotidyl transferase dUTP nick-end labelling positive (+) cells (%) in the peri-infarct region than the control group. This study demonstrated that TMF treatment 10 or 50 min after ischaemia alleviated brain damage. Furthermore, the timing of AhR antagonist administration affected the inhibition of cellular or vasogenic oedema formation caused by a transient ischaemic stroke.

Glutamate-weighted chemical exchange saturation transfer (GluCEST) is a useful imaging tool to detect glutamate signal alterations caused by neuroinflammation. This study aimed to visualize and quantitatively evaluate hippocampal glutamate alterations in a rat model of sepsis-induced brain injury using GluCEST and proton magnetic resonance spectroscopy (¹H-MRS). Twenty-one Sprague Dawley rats were divided into three groups (sepsis-induced groups (SEP05, n = 7 and SEP10, n = 7) and controls (n = 7)). Sepsis was induced through a single intraperitoneal injection of lipopolysaccharide (LPS) at a dose of 5 mg/kg (SEP05) or 10 mg/kg (SEP10). GluCEST values and ¹H-MRS concentrations in the hippocampal region were quantified using conventional magnetization transfer ratio asymmetry and a water scaling method, respectively. In addition, we examined immunohistochemical and immunofluorescence staining to observe the immune response and activity in the hippocampal region after LPS exposure. The GluCEST and ¹H-MRS results showed that GluCEST values and glutamate concentrations were significantly higher in sepsis-induced rats than those in controls as the LPS dose increased. GluCEST imaging may be a helpful technique for defining biomarkers to estimate glutamate-related metabolism in sepsis-associated diseases.

Background: Glutamate-weighted chemical exchange saturation transfer (GluCEST) is a useful imaging tool that can be used to detect changes in glutamate levels in vivo and could also be helpful in the diagnosis of brain myelin changes. We investigated glutamate level changes in the cerebral white matter of a rat model of cuprizone-administered demyelination and remyelination using GluCEST. Method: We used a 7 T pre-clinical magnetic resonance imaging (MRI) system. The rats were divided into the normal control (CTRL), cuprizone-administered demyelination (CPZ_DM), and remyelination (CPZ_RM) groups. GluCEST data were analyzed using the conventional magnetization transfer ratio asymmetry in the corpus callosum. Immunohistochemistry and transmission electron microscopy analyses were also performed to investigate the myelinated axon changes in each group. Results: The quantified GluCEST signals differed significantly between the CPZ_DM and CTRL groups (−7.25 ± 1.42% vs. −2.84 ± 1.30%; p = 0.001). The increased GluCEST signals in the CPZ_DM group decreased after remyelination (−6.52 ± 1.95% in CPZ_RM) to levels that did not differ significantly from those in the CTRL group (p = 0.734). Conclusion: The apparent temporal signal changes in GluCEST imaging during demyelination and remyelination demonstrated the potential usefulness of GluCEST imaging as a tool to monitor the myelination process.

Purpose: To investigate glutamate signal distributions in multiple brain regions of a healthy rat brain using glutamate-weighted chemical exchange saturation transfer (GluCEST) imaging. Method: The GluCEST data were obtained using a 7.0 T magnetic resonance imaging (MRI) scanner, and all data were analyzed using conventional magnetization transfer ratio asymmetry in eight brain regions (cortex, hippocampus, corpus callosum, and rest of midbrain in each hemisphere). GluCEST data acquisition was performed again one month later in five randomly selected rats to evaluate the stability of the GluCEST signal. To evaluate glutamate level changes calculated by GluCEST data, we compared the results with the concentration of glutamate acquired from ¹H magnetic resonance spectroscopy (¹H MRS) data in the cortex and hippocampus. Results: GluCEST signals showed significant differences (all p ≤ 0.001) between the corpus callosum (−1.71 ± 1.04%; white matter) and other brain regions (3.59 ± 0.41%, cortex; 5.47 ± 0.61%, hippocampus; 4.49 ± 1.11%, rest of midbrain; gray matter). The stability test of GluCEST findings for each brain region was not significantly different (all p ≥ 0.263). In line with the GluCEST results, glutamate concentrations measured by ¹H MRS also appeared higher in the hippocampus (7.30 ± 0.16 μmol/g) than the cortex (6.89 ± 0.72 μmol/g). Conclusion: Mapping of GluCEST signals in the healthy rat brain clearly visualize glutamate distributions. These findings may yield a valuable database and insights for comparing glutamate signal changes in pre-clinical brain diseases.