Glucocorticoids are released after hypothalamus-pituitary-adrenal axis stimulation by stress and act both in the periphery and in the brain to bring about adaptive responses that are essential for life. Dysregulation of the stress response can precipitate psychiatric diseases, in particular depression. Recent genetic studies have suggested that the glucocorticoid carrier transcortin, also called corticosteroid-binding globulin (CBG), may have an important role in stress response. We have investigated the effect of partial or total transcortin deficiency using transcortin knockout mice on hypothalamus-pituitary-adrenal axis functioning and regulation as well as on behaviors linked to anxiety and depression traits in animals. We show that CBG deficiency in mice results in markedly reduced total circulating corticosterone at rest and in response to stress. Interestingly, free corticosterone concentrations are normal at rest but present a reduced surge after stress in transcortin-deficient mice. No differences were detected between transcortin-deficient mice for anxiety-related traits. However, transcortin-deficient mice display increased immobility in the forced-swimming test and markedly enhanced learned helplessness after prolonged uncontrollable stress. The latter is associated with an approximately 30% decrease in circulating levels of free corticosterone as well as reduced Egr-1 mRNA expression in hippocampus in CBG-deficient mice. Additionally, transcortin-deficient mice show no sensitization to cocaine-induced locomotor responses, a well described corticosterone-dependent test. Thus, transcortin deficiency leads to insufficient glucocorticoid signaling and altered behavioral responses after stress. These findings uncover the critical role of plasma transcortin in providing an adequate endocrine and behavioral response to stress.

Multifunctional polymersomes loaded with maghemite nanoparticles and grafted with an antibody, directed against human endothelial receptor 2, are developed as novel MRI contrast agents for bone metastasis imaging. Upon administration in mice bearing bone tumor grown from human breast cancer cells, MR images show targeting and enhanced retention of antibody-labeled polymersomes at the tumor site.

Depressive disorders represent a major public health concern and display a continuously rising prevalence. Importantly, a large proportion of patients develops aversive side effects and/or does not respond properly to conventional antidepressants. These issues highlight the need to identify further therapeutic strategies, including nutritional approaches using natural plant extracts with known beneficial impacts on health. In that context, growing evidence suggests that saffron could be a particularly promising candidate. This preclinical study aimed therefore to test its antidepressant-like properties in mice and to decipher the underlying mechanisms by focusing on monoaminergic neurotransmission, due to its strong implication in mood disorders. For this purpose, the behavioral and neurobiochemical impact of a saffron extract, Safr’Inside™ (6.5 mg/kg per os) was measured in naïve mice. Saffron extract reduced depressive-like behavior in the forced swim test. This behavioral improvement was associated with neurobiological modifications, particularly changes in serotonergic and dopaminergic neurotransmission, suggesting that Safr’Inside™ may share common targets with conventional pharmacological antidepressants. This study provides useful information on the therapeutic relevance of nutritional interventions with saffron extracts to improve management of mood disorders.

Overhauser-enhanced MRI (OMRI) offers the potentiality of detecting low-concentrated species generated by specific biological processes. However molecular imaging applications of OMRI need significant improvement in spatial localization. Here it is shown that 3D-OMRI of a free radical injected in tumor-bearing mice can be performed at high anatomical resolution at a constant field. A 30 mm cavity operating at 5.43 GHz was inserted in a C-shaped magnet for proton MRI at 0.194 T. Nude mice with or without brain-implanted C6 rat glioma were positioned in the cavity and injected with TOPCA (1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid). OMRI was performed in 3D within several minutes in the brain region without high overheating of the animals. Voxel size was 0.5 × 0.5 × 1 mm³ , providing good delineation of brain regions. Signal amplifications ranged from 2 in tumors to 10 in vessels several minutes after TOPCA injection. Time-course of signal enhancement could be measured by 2D OMRI at 15 s time intervals in a localized thin slice. The method opens the way for molecular imaging of biological activities able to generate OMRI-visible free radicals.

Despite an increasing level of evidence supporting the individual beneficial effect of polyphenols on cognitive performance, information related to the potential synergistic action of these phytonutrients on cognitive performance during a prolonged cognitive effort is currently lacking. This study investigated the acute and sustained action of a polyphenols-rich extract from grape and blueberry (PEGB), on working memory and attention in healthy students during a prolonged and intensive cognitive effort. In this randomised, cross-over, double blind study, 30 healthy students consumed 600 mg of PEGB or a placebo. Ninety minutes after product intake, cognitive functions were assessed for one hour using a cognitive demand battery including serial subtraction tasks, a rapid visual information processing (RVIP) task and a visual analogical scale. Flow-mediated dilation (FMD) and plasma flavan-3-ols metabolites quantification were also performed. A 2.5-fold increase in serial three subtraction variation net scores was observed following PEGB consumption versus placebo (p < 0.001). A trend towards significance was also observed with RVIP percentage of correct answers (p = 0.058). No treatment effect was observed on FMD. Our findings suggest that consumption of PEGB coupled with a healthy lifestyle may be a safe alternative to acutely improve working memory and attention during a sustained cognitive effort.

Depressive disorders are a major public health concern. Despite currently available treatment options, their prevalence steadily increases, and a high rate of therapeutic failure is often reported, together with important antidepressant-related side effects. This highlights the need to improve existing therapeutic strategies, including by using nutritional interventions. In that context, saffron recently received particular attention for its beneficial effects on mood, although the underlying mechanisms are poorly understood. This study investigated in mice the impact of a saffron extract (Safr’Inside™; 6.25 mg/kg, per os) on acute restraint stress (ARS)-induced depressive-like behavior and related neurobiological alterations, by focusing on hypothalamic–pituitary–adrenal axis, inflammation-related metabolic pathways, and monoaminergic systems, all known to be altered by stress and involved in depressive disorder pathophysiology. When given before stress onset, Safr’Inside administration attenuated ARS-induced depressive-like behavior in the forced swim test. Importantly, it concomitantly reversed several stress-induced monoamine dysregulations and modulated the expression of key enzymes of the kynurenine pathway, likely reducing kynurenine-related neurotoxicity. These results show that saffron pretreatment prevents the development of stress-induced depressive symptoms and improves our understanding about the underlying mechanisms, which is a central issue to validate the therapeutic relevance of nutritional interventions with saffron in depressed patients.

Methotrexate is a widely used cytostatic in chemotherapy cocktails for the treatment of cancer but is associated with cognitive impairment. Previous animal studies indicated that methorexate decreases hippocampal cell proliferation, which might contribute to the observed cognitive impairment. However, clinical studies have shown that cognitive impairment can also be noticed in some cancer patients before any systemic treatment is initiated. We aim in the present study to discern whether hippocampal cell proliferation is negatively affected by tumor growth and if the presence of a tumor amplifies the effects of methotrexate. Buffalo rats were subcutaneously injected with PBS or Morris Hepatoma 7777 cells to induce a tumor. Two weeks after this injection the animals received an intraperitoneal injection of methotrexate or saline. Three weeks later hippocampal cell proliferation was quantified using immunohistochemical staining. Treatment with Morris Hepatoma 7777 cells decreased the number of proliferating cells as compared to control animals. An overall tumor effect was absent mainly because methotrexate treatment significantly decreased cell proliferation with no differences between animals with or without a tumor. Neither methotrexate nor the tumor induced pica behavior. These findings indicate that although the presence of a tumor reduces hippocampal cell proliferation it does not affect the negative effect of methotrexate on this plasticity marker. Since sickness behavior is not induced by methotrexate or tumor presence it does not play a role in the development of cognitive deficits. This study further indicates that the effects of methotrexate on brain and behavior can be studied in healthy animals.

A knowledge of the spatial localization of cell vehicles used in gene therapy against glioma is necessary before launching therapy. For this purpose, MRI cell tracking is performed by labeling the cell vehicles with contrast agents. In this context, the goal of this study was to follow noninvasively the chemoattraction of therapeutic microglial cells to a human glioma model before triggering therapy. Silica nanoparticles grafted with gadolinium were used to label microglia. These vehicles, expressing constitutively the thymidine kinase suicide gene fused to the green fluorescent protein gene, were injected intravenously into human glioma-bearing nude mice. MRI was performed at 4.7 T to track noninvasively microglial accumulation in the tumor. This was followed by microscopy on brain slices to assess the presence in the glioma of the contrast agents, microglia and fusion gene through the detection of silica nanoparticles grafted with tetramethyl rhodamine iso-thiocyanate, 3,3'-dioctadecyloxacarbocyanine perchlorate and green fluorescent protein fluorescence, respectively. Finally, gancyclovir was administered systemically to mice. Human microglia were detectable in living mice, with strong negative contrast on T(2) *-weighted MR images, at the periphery of the glioma only 24 h after systemic injection. The location of the dark dots was identical in MR microscopy images of the extracted brains at 9.4 T. Fluorescence microscopy confirmed the presence of the contrast agents, exogenous microglia and suicide gene in the intracranial tumor. In addition, gancyclovir treatment allowed an increase in mice survival time. This study validates the MR tracking of microglia to a glioma after systemic injection and their use in a therapeutic strategy against glioma.