Obesity-induced diabetes is associated with chronic inflammation and is considered a risk factor for neurodegeneration. We tested the hypothesis that an AMP-activated protein kinase activator, resveratrol (RES), which is known to exert potent anti-inflammatory effects, would attenuate peripheral and central inflammation and improve memory deficit in mice fed a high-fat diet (HFD). C57BL/6J mice were fed an HFD or an HFD supplemented with RES for 20 weeks. Metabolic parameters in serum were evaluated, and Western blot analysis and immunohistochemistry in peripheral organs and brain were completed. We used the Morris water maze test to study the role of RES on memory function in HFD-treated mice. RES treatment reduced hepatic steatosis, macrophage infiltration, and insulin resistance in HFD-fed mice. In the hippocampus of HFD-fed mice, the protein levels of tumor necrosis factor-α and Iba-1 expression were reduced by RES treatment. Choline acetyltransferase was increased, and the phosphorylation of tau was decreased in the hippocampus of HFD-fed mice upon RES treatment. In particular, we found that RES significantly improved memory deficit in HFD-fed mice. These findings indicate that RES reverses obesity-related peripheral and central inflammation and metabolic derangements and improves memory deficit in HFD-fed diabetic mice.

IntroductionDepression is the most common psychiatric illness, with about 121 million people affected worldwide. Of people who experience a depressive episode, 15% commit suicide.1,2 Although many studies have investigated the pathophysiologic mechanisms of major depressive disorder (MDD) using live brain imaging and postmortem studies, its etiology remains unclear; however, recent progress based on those studies has gradually revealed common features of MDD. Among these features, volume reduction of selective brain regions in patients with MDD is the most remarkable.3-5 This is mainly due to a lower number of glial cells and neuronal atrophy in those regions. 6,7 Specifically, the reduction of astrocytes among all glial cells was frequently found in postmortem studies. 3,[8][9][10] Another study reported lower levels of glutamine synthetase (GS), one of the astrocyte-specific enzymes involved in the glutamate-glutamine (Glu-Gln) cycle, and its activity levels were decreased in some clinical studies of MDD. 11A variety of preclinical studies have reported findings to support the idea of astrocyte loss and Glu-Gln disruption. Consistent with those studies, several papers have reported decreased gliogenesis and number of astrocytes in the medial prefrontal cortex (mPFC) in animal models of chronic stressinduced depression.7,12-14 These results strongly suggest that a relationship exists between the functions of astrocytes and the behavioural aspects of MDD. To test this issue, a recent study ablated astrocytes in the prelimbic cortex (PLC) using a specific toxin and revealed that depressive-like behaviours could be evoked using only this treatment.14 It remains to be determined how astrocyte loss results in depressive behaviours.To address this question, we focused on the role of astrocytes Background: The brain levels of glutamate (Glu) and glutamine (Gln) are partially regulated through the Glu-Gln cycle. Astrocytes play a role in regulating the Glu-Gln cycle, and loss of astrocytes has been associated with depressive disorders. We hypothesized that levels of Glu and Gln would be affected by astrocyte loss and dysregulation of the Glu-Gln cycle and that depressive-like behaviours would be closely related to the level of changes in Glu and Gln. Methods: We used liquid chromatography to measure Glu and Gln concentrations in the prefrontal cortex of male mice infused with L-α aminoadipic acid (L-AAA), a specific astrocyte toxin, in the prelimbic cortex. Methionine sulfoximine, a Gln synthetase inhibitor, and α-methyl-amino-isobutyric acid, a blocker of neuronal Gln transporters, were used to disturb the Glu-Gln cycle. We assessed the behavioural change by drug infusion using the forced swim test (FST) and sucrose preference test. Results: The Glu and Gln levels were decreased on the fifth day after L-AAA infusion, and the infused mice showed longer durations of immobility in the FST and lower sucrose preference, indicative of depressive-like behaviour. Mice in which Gln synthetase or Gln transport were inhibited al...

The present study compared mesenchymal stem cells derived from umbilical cord matrix (UCM-MSCs) with bone marrow (BM-MSCs) of miniature pigs on their phenotypic profiles and ability to differentiate in vitro into osteocytes, adipocytes and neuron-like cells. This study further evaluated the therapeutic potential of UCM-MSCs in a mouse Parkinson's disease (PD) model. Differences in expression of some cell surface and cytoplasm specific markers were evident between UCM-MSCs and BM-MSCs. However, the expression profile indicated the primitive nature of UCM-MSCs, along with their less or non-immunogenic features, compared with BM-MSCs. In vitro differentiation results showed that BM-MSCs had a higher tendency to form osteocytes and adipocytes, whereas UCM-MSCs possessed an increased potential to transform into immature or mature neuron-like cells. Based on these findings, UCM-MSCs were transplanted into the right substantia nigra (SN) of a mouse PD model. Transplantation of UCM-MSCs partially recovered the mouse PD model by showing an improvement in basic motor behaviour, as assessed by rotarod and bridge tests. These observations were further supported by the expression of markers, including nestin, tyrosine hydroxylase (TH), neuronal growth factor (NGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), at the site of cell transplantation. Our findings of xenotransplantation have collectively suggested the potential utility of UCM-MSCs in developing viable therapeutic strategies for PD.

BackgroundThe amygdala plays an essential role in controlling emotional behaviors and has numerous connections to other brain regions. The functional role of the amygdala has been highlighted by various studies of stress-induced behavioral changes. Here we investigated gene expression changes in the amygdala in the chronic immobilization stress (CIS)-induced depression model.ResultsEight genes were decreased in the amygdala of CIS mice, including genes for neurotrophic factors and extracellular matrix proteins. Among these, osteoglycin, fibromodulin, insulin-like growth factor 2 (Igf2), and insulin-like growth factor binding protein 2 (Igfbp2) were further analyzed for histological expression changes. The expression of osteoglycin and fibromodulin simultaneously decreased in the medial, basolateral, and central amygdala regions. However, Igf2 and Igfbp2 decreased specifically in the central nucleus of the amygdala. Interestingly, this decrease was found only in the amygdala of mice showing higher immobility, but not in mice displaying lower immobility, although the CIS regimen was the same for both groups.ConclusionsThese results suggest that the responsiveness of the amygdala may play a role in the sensitivity of CIS-induced behavioral changes in mice.

Regulator of G-protein signaling (RGS) proteins play an important role in G-protein coupled receptor (GPCR) signaling and the activity of some GPCRs is modulated via RGS protein levels during stress response. The aim of this study was to investigate changes in RGS protein mRNA expressions in the mouse brain after 2h restraint stress. The mRNA level of 19 RGS proteins was analyzed using real-time PCR in six brain regions, which included the prefrontal cortex, amygdala, hippocampus, hypothalamus, striatum, and pituitary gland, from control and stressed mouse. We found that the level of mRNA of each RGS varied according to brain region and that two to eight RGS proteins exhibited changes in mRNA levels in each brain region by restraint stress. It was also revealed that RGS4 protein amount was consistent with mRNA level, indicating RGS4 protein may have regulatory roles in the acute stress response.