The higher prevalence and risk for Alzheimer's disease in women relative to men has been partially attributed to the precipitous decline in gonadal hormone levels that occur in women following the menopause. While considerable attention has focused on the consequence of estrogen loss, and thus, estrogen's neuroprotective potential, it is important to recognize that the menopause results in a precipitous decline in progesterone levels as well. In fact, progesterone is neuroprotective, although the precise mechanisms involved remain unclear. Based on our previous observation that progesterone elicits the phosphorylation of ERK and Akt, key effectors of the neuroprotective MAPK and PI3-K pathways, respectively, we determined if activation of either of these pathways was necessary for progesterone-induced protection. Using organotypic explants (slice culture) of the cerebral cortex, we found that progesterone protected against glutamate-induced toxicity. Further, these protective effects were inhibited by either the MEK1/2 inhibitor, UO126, or the PI-3K inhibitor, LY294002, supporting the requirement of both the MAPK and PI-3K pathways in progesteroneinduced protection. In addition, at a concentration and duration of treatment consistent with our neuroprotection data, progesterone also increased the expression of Brain-Derived Neurotrophic Factor (BDNF), at the level of both protein and mRNA. This induction of BDNF may be relevant to the protective effects of progesterone since inhibition of Trk signaling, using K252a, inhibited the protective effects of progesterone. Collectively, these data suggest that progesterone is protective via multiple and potentially related mechanisms.

Whereas hormone therapy is used for the treatment of menopausal symptoms, its efficacy in helping reduce the risk of other diseases such as Alzheimer's disease has been questioned in view of the results of recent clinical trials that appeared inconsistent with numerous basic research studies that supported the beneficial effects of hormones. One possible explanation of this discrepancy may lie in the choice of hormone used. For example, we and others found that progesterone is neuroprotective whereas medroxyprogesterone acetate (MPA), the synthetic progestin used in hormone therapy, is not. Because our data suggest that progesterone-induced protection is associated with the induction of brain-derived neurotrophic factor (BDNF) levels and, importantly, can be blocked by inhibiting the neurotrophin signaling, we determined whether progesterone and medroxyprogesterone acetate differed in their ability to regulate BDNF levels in the explants of the cerebral cortex. We found that progesterone elicited an increase in both BDNF mRNA and protein levels, whereas medroxyprogesterone acetate did not. Furthermore, using both a pharmacological inhibitor of the progesterone receptor (PR) and PR knockout mice, we determined that the effects of progesterone were mediated by the classical PR. Our results underscore the fact that not all progestins have equivalent effects on the brain and suggest that the selection of the appropriate progestin may influence the success of hormone therapy formulations used in treating the menopause and/or reducing the risk for diseases associated with the postmenopausal period.

Neurotrophins play essential roles in the development, differentiation, and survival of neuronal and nonneuronal cells. Alterations in neurotrophin expression have been implicated in a variety of neurodegenerative disorders. Dysregulation of brain-derived neurotrophic factor (BDNF) has been implicated in deficits of long-term potentiation and cognition and may contribute to the development of Alzheimer's disease (AD). In this study, we used complementary pharmacological and molecular approaches to evaluate the role of ERK1/2 and ERK5, two members of the MAPK pathway associated with neuroprotection, in regulating BDNF expression in C6 glial cells and primary astrocytes. Our data revealed that U0126, an inhibitor of both ERK5 and ERK1/2, increased the levels of BDNF mRNA, whereas the MEK1/2-specific inhibitor PD184352 did not, suggesting that ERK5 exerts negative control over BDNF expression. This was supported by experiments in which RNAi-mediated depletion of ERK5 led to an increase in BDNF. In contrast, transfection with constitutively active MEK5 resulted in an inhibition of BDNF expression, confirming the inhibitory role of ERK5 in the regulation of BDNF. Interestingly, transfection with the dominant active mutant of MEK1 (MEKR4F), the upstream activator of ERK1/2, resulted in a modest increase in BDNF levels. Collectively, our data suggest that ERK5 and ERK1/2 exert opposite effects on BDNF expression and support the hypothesis that an imbalance of these two signaling pathways may contribute to the pathology of diseases in which neurotrophin dysregulation is noted.

IntroductionPleural malignancy, particularly malignant pleural mesothelioma (MPM) is increasing in incidence due to the long latency period from exposure to asbestos to development of the disease. MPM can be challenging to diagnose. For patients presenting without a pleural effusion, CT-guided biopsy remains the primary choice of biopsy, but the diagnostic sensitivity of this investigation is 70%–75%. Therefore, a proportion of patients will go on to require further biopsies. If the first biopsy is non-diagnostic, the chances of further non-diagnostic biopsies are high in MPM.MethodsTarget is a multicentre randomised controlled trial, aiming to recruit 78 patients over a 30-month period, from 10 centres in the UK. Patients will be randomised to either the standard arm which is a second CT-guided biopsy, or the interventional arm, a positron emission tomography-CT scan followed by a targeted CT-guided biopsy. Patients will be followed up for 12 months (patients recruited in the last 6 months of recruitment will have 6 months of follow-up). MPM biomarker mesothelin will be checked at baseline, 6 month and 12 month follow-up appointments where patients are able to attend these appointments.Ethics and disseminationEthical approval for this trial was granted by the South West—Exeter research and ethics committee (reference number 15/SW/0156). Results of the trial will be published in a peer-reviewed journal and presented at an international conference.Trial registration numberISRCTN14024829; Pre-results.

BackgroundData suggests that brain-derived neurotropic factor (BDNF) plays a neuroadaptive role in addiction. Whether serum BDNF levels are different in alcohol or psychostimulants as a function of craving is unknown. Here, we examined craving and serum BDNF levels in persons with alcohol versus psychostimulant dependence. Our goals were to explore BDNF as an objective biomarker for 1) craving 2) abstinence, and 3) years of chronic substance use.MethodsAn exploratory, cross-sectional study was designed. Men and women between 20–65 years old with alcohol, cocaine, or methamphetamine dependence were eligible. A craving questionnaire was used to measure alcohol, cocaine and methamphetamine cravings. Serum levels of BDNF were measured using enzyme linked immunoassay. Analysis of variance, chi-square, and correlations were performed using a 95% confidence interval and a significance level of P < 0.05.ResultsWe found a significant difference in the mean craving score among alcohol, cocaine and methamphetamine dependent subjects. There were no significant influences of race, gender, psychiatric disorder or psychotropic medication on serum BDNF levels. We found that among psychostimulant users BDNF levels were significantly higher in men than in women when the number of abstinent days was statistically controlled. Further, a significant correlation between serum BDNF levels and the number of abstinent days since last psychostimulant use was found.ConclusionThese data suggest that BDNF may be a biomarker of abstinence in psychostimulant dependent subjects and inform clinicians about treatment initiatives. The results are interpreted with caution due to small sample size and lack of a control group.