The pharmacological stimulation of NMDA receptors via co-agonist site: an fMRI study in the rat brain.

d-Serine has been proposed as an endogenous modulator at the co-agonist glycine-binding site of N-methyl-d-aspartate (NMDA) receptors. There is still some debate as to whether this site is saturated in vivo, but it seems likely that this depends on regional differences in local glycine or d-serine concentrations. In order to identify areas where the co-agonist site was not fully activated in vivo, we studied the effect of intraperitoneal d-serine administration in the rat brain using functional magnetic resonance imaging (fMRI). Using contrast agent injection, the variations in the relative cerebral blood volume (CBVrel) in several regions of interest were evaluated. d-Serine (50 mg/kg) elicited a significant statistical increase in the CBVrel in the hippocampus. This effect was inhibited by the specific full antagonist of the co-agonist glycine site L-701,324 indicating that the hippocampal activation occurred through the binding of the agonist d-serine to the glycine-binding site of NMDA receptors. This result demonstrates that in the hippocampus, the co-agonist sites of NMDA receptors are not endogenously saturated under our experimental conditions, suggesting an important role of d-serine in the modulation of receptor function in the hippocampus.

Effects of a mitogen-activated protein kinase inhibitor on allergic airways inflammation in the rat studied by magnetic resonance imaging.

We recently described a new model to study non-invasively with magnetic resonance imaging (MRI) the effects of compounds to prevent and/or resolve airway inflammation induced by ovalbumin in the lungs of actively sensitised rats. We report here the effects of 4-(4-fluorophenyl)-2-(1-methylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole fumarate (Compound 1), which exhibits inhibitory activity against p38alpha and p38beta2 and residual activity on c-Jun amino-terminal kinase (JNK)2 mitogen-activated protein (MAP) kinases, on the oedematous signals detected by MRI and generated by antigen challenge in the lungs of sensitized rats. Compound 1 (10 mg kg(-1)) given orally 1 h prior to allergen challenge significantly reduced the oedematous signal measured at 24 h. Similar effects were seen with a synthetic corticosteroid, mometasone furoate (0.3 mg kg(-1)), given intratracheally 3 h prior to challenge. For both compounds, inhibition of the oedematous signal was accompanied by reductions in the inflammatory parameters in the bronchoalveolar lavage fluid measured 24 h after challenge with ovalbumin. Compound 1 (10 mg kg(-1)) administered 24 h after challenge with ovalbumin did not change the rate of resolution of the signal detected by MRI in the lungs. In contrast, mometasone furoate (0.3 mg kg(-1)) significantly increased resolution of these signals, which was evident 3 h after drug administration and maintained to 48 h post challenge. Collectively, our data suggest that the p38 MAP kinase inhibitor Compound 1 shows a different profile than glucocorticosteroids since its ability to resolve existing inflammation is limited.

Macrophage infiltration into the rat knee detected by MRI in a model of antigen-induced arthritis.

Three-dimensional (3D) MR images were obtained from the knees of rats in a model of antigen-induced arthritis, elicited by the intraarticular administration of methylated bovine serum albumin (mBSA) to previously immunized rats. Superparamagnetic particles of iron oxide (SPIO) were administered i.v. 24 hr before each imaging session. Starting 4 days postantigen injection, images from arthritic knees exhibited distinctive signal attenuation in the synovium. This signal attenuation was significantly smaller in knees from animals treated with dexamethasone, a glucocorticosteroid, and completely absent in contralateral knees that had been challenged with vehicle. A significant negative correlation was found between the MRI signal intensity in the synovium and the histologically determined iron content in macrophages located in the same region. These results suggest the feasibility of detecting macrophage infiltration into the knee synovium in this model of antigen-induced arthritis by labeling the cells with SPIO. This readout could provide an early marker of disease progression, before more aggressive changes like cartilage and bone erosion take place. Monitoring early changes associated with arthritis can have an impact in preclinical studies by shortening the duration of the experimental period and by facilitating the investigation of novel immunomodulatory therapies acting on macrophages. Also, the approach can be potentially adapted to clinical studies.