The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia.

Brain preconditioning (PC) refers to a state of transient tolerance against a lethal insult that can be evoked by a prior mild event. It is thought that PC may induce different pathways responsible for neuroprotection, which may involve the attenuation of cell damage pathways, including the apoptotic cell death. In this context, p53 is a stress sensor that accumulates during brain ischemia leading to neuronal death. The murine double minute 2 gene (MDM2), a p53-specific E3 ubiquitin ligase, is the main cellular antagonist of p53, mediating its degradation by the proteasome. Here, we study the role of MDM2-p53 pathway on PC-induced neuroprotection both in cultured neurons (in vitro) and rat brain (in vivo). Our results show that PC increased neuronal MDM2 protein levels, which prevented ischemiainduced p53 stabilization and neuronal death. Indeed, PC attenuated ischemia-induced activation of the p53/PUMA/caspase-3 signaling pathway. Pharmacological inhibition of MDM2-p53 interaction in neurons abrogated PC-induced neuroprotection against ischemia. Finally, the relevance of the MDM2-p53 pathway was confirmed in rat brain using a PC model in vivo. These findings demonstrate the key role of the MDM2-p53 pathway in PC-induced neuroprotection against a subsequent ischemic insult and poses MDM2 as an essential target in ischemic tolerance

Electron Ionization of Imidazole and Its Derivative 2-Nitroimidazole

International audienceImidazole (IMI) is a basic building block of many biologically important compounds. Thus, its electron ionization properties are of major interest and essential for the comparison with other molecular targets containing its elemental structure. 2-Nitroimidazole (2NI) contains the imidazole ring together with nitrogen dioxide bound to the C2 position, making it a radiosensitizing compound in hypoxic tumors. In the present study, we investigated electron ionization of IMI and 2NI and determined the mass spectra, the ionization energies, and appearance energies of the most abundant fragment cations. The experiments were complemented by quantum chemical calculations on the thermodynamic thresholds and potential energy surfaces, with particular attention to the calculated transition states for the most important dissociation reactions. In the case of IMI, substantially lower threshold values (up to ~ 1.5 eV) were obtained in the present work compared to the only available previous electron ionization study. Closer agreement was found with recent photon ionization values, albeit the general trend of slightly higher values for the case of electron ionization. The only exception for imidazole was found in the molecular cation at m/z 40 which is tentatively assigned to the quasi-linear HCCNH+/ HCNCH+. Electron ionization of 2NI leads to analogous fragment cations as in imidazole, yet different dissociation pathways must be operative due to the presence of the NO2 group. Regarding the potential radiosensitization properties of 2NI, electron ionization is characterized by dominant parent cation formation and release of the neutral NO radical

Diabetes mellitus and severe mental illness: mechanism and clinical implications

The prevalence of diabetes mellitus is twofold to threefold higher in people with severe mental illness (SMI) than in the general population, with diabetes mellitus affecting ~12% of people receiving antipsychotics. The consequences of diabetes mellitus are more severe and frequent in people with SMI than in those without these conditions, with increased rates of microvascular and macrovascular complications, acute metabolic dysregulation and deaths related to diabetes mellitus. Multiple complex mechanisms underlie the association between diabetes mellitus and SMI; these mechanisms include genetic, environmental and disease-specific factors, and treatment-specific factors. Although antipsychotics are the mainstay of treatment in SMI, a causative link, albeit of uncertain magnitude, seems to exist between antipsychotics and diabetes mellitus. The principles of managing diabetes mellitus in people with SMI are similar to those for the general population and should follow currently established treatment algorithms. Lifestyle interventions are needed to reduce incident diabetes mellitus. In addition, improved uptake of opportunities to screen for this disease will reduce the high prevalence of undiagnosed diabetes mellitus. Currently, people with SMI receive poorer treatment for diabetes mellitus than the general population. Thus, health-care professionals in primary care, diabetes mellitus services and mental health teams have a responsibility to ensure that patients with SMI are not disadvantage

Almost All Antipsychotics Result in Weight Gain: A Meta-Analysis

INTRODUCTION: Antipsychotics (AP) induce weight gain. However, reviews and meta-analyses generally are restricted to second generation antipsychotics (SGA) and do not stratify for duration of AP use. It is hypothesised that patients gain more weight if duration of AP use is longer. METHOD: A meta-analysis was conducted of clinical trials of AP that reported weight change. Outcome measures were body weight change, change in BMI and clinically relevant weight change (7% weight gain or loss). Duration of AP-use was stratified as follows: ≤6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots stratified by AP as well as by duration of use were generated and results were summarised in figures. RESULTS: 307 articles met inclusion criteria. The majority were AP switch studies. Almost all AP showed a degree of weight gain after prolonged use, except for amisulpride, aripiprazole and ziprasidone, for which prolonged exposure resulted in negligible weight change. The level of weight gain per AP varied from discrete to severe. Contrary to expectations, switch of AP did not result in weight loss for amisulpride, aripiprazole or ziprasidone. In AP-naive patients, weight gain was much more pronounced for all AP. CONCLUSION: Given prolonged exposure, virtually all AP are associated with weight gain. The rational of switching AP to achieve weight reduction may be overrated. In AP-naive patients, weight gain is more pronounced