Effects of Long-Term Endogenous Corticosteroid Exposure on Brain Volume and Glial Cells in the AdKO Mouse.

Chronic exposure to high circulating levels of glucocorticoids has detrimental effects on health, including metabolic abnormalities, as exemplified in Cushing's syndrome (CS). Magnetic resonance imaging (MRI) studies have found volumetric changes in gray and white matter of the brain in CS patients during the course of active disease, but also in remission. In order to explore this further, we performed MRI-based brain volumetric analyses in the AdKO mouse model for CS, which presents its key traits. AdKO mice had reduced relative volumes in several brain regions, including the corpus callosum and cortical areas. The medial amygdala, bed nucleus of the stria terminalis, and hypothalamus were increased in relative volume. Furthermore, we found a lower immunoreactivity of myelin basic protein (MBP, an oligodendrocyte marker) in several brain regions but a paradoxically increased MBP signal in the male cingulate cortex. We also observed a decrease in the expression of glial fibrillary acidic protein (GFAP, a marker for reactive astrocytes) and ionized calcium-binding adapter molecule 1 (IBA1, a marker for activated microglia) in the cingulate regions of the anterior corpus callosum and the hippocampus. We conclude that long-term hypercorticosteronemia induced brain region-specific changes that might include aberrant myelination and a degree of white matter damage, as both repair (GFAP) and immune (IBA1) responses are decreased. These findings suggest a cause for the changes observed in the brains of human patients and serve as a background for further exploration of their subcellular and molecular mechanisms.

Metabolic changes detected in vivo by 1H MRS in the MPTP-intoxicated mouse.

We used in vivo proton ((1)H) Magnetic Resonance Spectroscopy (MRS) to measure the levels of the main excitatory amino acid, glutamate (Glu) and also glutamine (Gln) and GABA in the striatum and cerebral cortex in the MPTP-intoxicated mouse, a model of dopaminergic denervation, before and after dopamine (DA) replacement. The study was performed at 9.4T on control mice (n = 8) and MPTP-intoxicated mice (n = 8). In vivo spectra were acquired in a voxel (8 microL) centered in the striatum, and in the cortex (4.6 microL). Three days after basal MRS acquisitions new spectra were acquired in the striatum and cortex, after levodopa (200 mg.kg(-1)). Glu, Gln and GABA concentrations obtained in the basal state were significantly increased in the striatum of MPTP-lesioned mice (Glu: 20.2 +/- 0.8 vs 11.4 +/- 0.9 mM, p < 0.001; Gln: 5.4 +/- 1.6 vs 2.0 +/- 0.6 mM, p < 0.05; GABA: 3.6 +/- 0.8 vs 1.6 +/- 0.2 mM, p < 0.05). Levodopa lowered metabolites concentrations in the striatum of MPTP-lesioned mice (Glu: 20.2 +/- 0.8 vs 11.2 +/- 0.4 mM (+ Ldopa), p < 0.001; Gln: 5.4 +/- 1.6 vs 1.6 +/- 0.4 mM (+ Ldopa), p < 0.05; GABA: 3.6 +/- 0.8 vs 1.7 +/- 0.4 mM (+ Ldopa), p < 0.01). Metabolite levels in the striatum of MPTP-intoxicated mice + levodopa were not significantly different from those in the striatum of controls. No change was found in the cortex after DA denervation and after DA replacement between the two animals groups. These results strongly support a predominant change in striatal Glu synaptic activity in the cortico-striatal pathway. Acute levodopa administration reverses the increase of metabolites in the striatum.

Orthologous metabonomic qualification of a rodent model combined with magnetic resonance imaging for an integrated evaluation of the toxicity of Hypochoeris radicata.

In the present study, we have used metabonomics combined with magnetic resonance imaging (MRI) to investigate an orphan neurological disease, Australian stringhalt, described in horse-ingesting inflorescences of Hypochoeris radicata (HR), without any knowledge on the toxic principle and without any practical possibility to perform experiments on the target species. To get valuable candidate biomarkers, we have chosen the mouse species as a "metabolically competent" laboratory animal model. Metabonomics has been applied as a holistic approach to obtain some pertinent metabolic information about the target organs and biomarker metabolites involved in the HR-induced disruptive events. From urine, liver, and brain metabolic fingerprints, HR ingestion induced a very significant effect on the general metabolism, which is proportional to the HR dose administered and to the HR intoxication duration. The main metabolic biomarker in the mouse model of an intoxication specifically induced by HR feeding has been unambiguously identified as scyllo-inositol. A significant increase of this metabolic marker has been measured in urine and in hydrosoluble liver or brain extracts with a very significant canonical link between these two organs. MRI results obtained in the thalamus have confirmed the involvement of scyllo-inositol, a metabolite found in many neurodegenerative diseases, in some specific metabolic disruptions involved in both neuronal and glial dysfunctions as awaited from etiology of this horse disease. This brain metabolic biomarker has been clearly associated with changes in N-acetyl-aspartate, lactate, and choline cerebral concentration found in both neuronal and glial dysfunctions. Scyllo-inositol is a valuable candidate biomarker of the Australian stringhalt disease that needs now to be clinically validated in the target species.