1,721,186 research outputs found
Translocator Protein (TSPO) and Neurosteroids: Implications in Psychiatric Disorders.
No full textThe translocator protein (TSPO) is a five transmembrane domain protein localised primarily in the outer mitochondrial membrane of steroid-synthesizing tissues, including the brain. The TSPO mediates the rate-limiting step of steroidogenesis, consisting of the translocation of the substrate cholesterol from the outer to the inner mitochondrial membrane. In the recent years TSPO function has received attention in several psychiatric disorders since these diseases have been associated with unbalanced steroid levels. Accordingly, an alteration in the levels of TSPO has been found in various psychiatric disorders, including social phobia, post-traumatic stress disorder, adult separation anxiety and schizophrenia. The discovery that TSPO drug ligands are able to stimulate neurosteroid production in the brain, independently of peripheral endocrine sources, and restore neurosteroid-mediated neurotransmission, has made the TSPO an attractive drug target for treating a number of psychiatric disorders. In anxiety TSPO drug ligands have shown in vivo efficacy in pharmacologically induced anxiety models in both animals and humans. The focus of this review is to illustrate the currently available literature regarding the role of TSPO in psychiatric disorders
Trazodone treatment protects neuronal-like cells from inflammatory insult by inhibiting NF-κB, p38 and JNK
Full text linkGrowing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of major depression and that inflammatory processes may influence the antidepressant treatment response. Depressed patients exhibit increased levels of inflammatory markers in both the periphery and brain, and high co-morbidity exists between depression and diseases associated with inflammatory alterations. Trazodone (TDZ) is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors. Although the trophic and protective properties of classic antidepressants have extensively been exploited, the effects of TDZ remain to be fully elucidated. In this study, the pharmacological activities of TDZ on human neuronal-like cells were investigated under both physiological and inflammatory conditions. An in vitro inflammatory model was established using lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α), which efficiently mimic the stress-related changes in neurotrophic and pro-inflammatory genes.Our results showed that TDZ significantly increased the mRNA expression of both brain-derived nerve factor (BDNF) and cAMP response element-binding protein (CREB) and decreased the cellular release of the pro-inflammatory cytokine interferon gamma (IFN-γ) in neuronal-like cells.In contrast, neuronal cell treatment with LPS and TNF-α decreased the expression of CREB and BDNF and increased the expression of nuclear factor kappa B (NF-κB), a primary transcription factor that functions in inflammatory response initiation. Moreover, the two agents induced the release of pro-inflammatory cytokines (. i.e., interleukin-6 and IFN-γ) and decreased the production of the anti-inflammatory cytokine interleukin-10. TDZ pre-treatment completely reversed the decrease in cell viability and counteracted the decrease in BDNF and CREB expression mediated by LPS-TNF-α. In addition, the production of inflammatory mediators was inhibited, and the release of interleukin-10 was restored to control levels.Furthermore, the intracellular signalling mechanism regulating TDZ-elicited effects was specifically investigated. TDZ induced extracellular signal-regulated kinase (ERK) phosphorylation and inhibited constitutive p38 activation. Moreover, TDZ counteracted the activation of p38 and c-Jun NH2-terminal kinase (JNK) elicited by LPS-TNF-α, suggesting that the neuro-protective role of TDZ could be mediated by p38 and JNK.Overall, our results demonstrated that the protective effects of TDZ under inflammation in neuronal-like cells function by decreasing pro-inflammatory signalling and by enhancing anti-inflammatory signalling
The GABAA-BZR Complex as Target for the Development of Anxiolytic Drugs.
No full textAnxiety disorders have been linked to alterations in γ-aminobutyric acid (GABA) neurotransmission. GABA interacts with the ligand-gated ion channels, GABAA receptor (GABAA-R) subtypes, and regulates the flow of chloride into the cell, causing neuron hyperpolarization. GABAA-Rs are assembled from a family of 19 homologous subunit gene products and form mostly hetero-oligomeric pentamers. The major isoforms of the GABAA-Rs contain α, β and γ subunits and show a regional heterogeneity that is associated with distinct physiological effects. A variety of allosteric ligands can modulate the response to GABA by binding at different sites on the GABAA-R complex. The best characterized binding site is the benzodiazepine (BZ) one, which is located at the α/γ subunit interface. BZs are commonly used in therapy for their effects as anxiolytic, anticonvulsants, myorelaxants and hypnotics. The broad range of pharmacological effects of classical BZs are mediated by the selective activation of different GABAA-R subtypes: the α1 subunit containing BZ receptor (BZ-R) mediates sedation, the α2 and α3 subunit containing BZ-R mediates anxiolysis and myorelaxation, and the α5 subunit containing BZ-R mediates cognitive impairment. Based on the current understanding of the diversity of the GABAA-R family, different approaches have been employed to develop drugs that target the GABAA/BZ-R complex with selective anxiolytic action and improved profiles. In this review, we present current knowledge about the role of the GABAA/BZ-R complex in anxiety disorders, new insights into the molecular biology of the receptor complex, and the importance of this target in the development of new therapeutic agents in anxiety
Cytokine secretion responsiveness of lymphomonocytes following cortisol cell exposure: Sex differences
Full text linkThe stress hormone cortisol has been recognized as a coordinator of immune response. However, its different ability to modulate the release of inflammatory mediators in males and females has not been clarified yet. Indeed, the dissection of cortisol specific actions may be difficult due to the complex hormonal and physio-pathological individual status. Herein, the release of inflammatory mediators following increasing cortisol concentrations was investigated in an in vitro model of primary human male and female lymphomonocytes. The use of a defined cellular model to assess sex differences in inflammatory cytokine secretion could be useful to exclude the effects of divergent and fluctuating sex hormone levels occurring in vivo. Herein, the cells were challenged with cortisol concentrations resembling the plasma levels achieving in physiological and stressful conditions. The production of cytokines and other molecules involved in inflammatory process was determined. In basal conditions, male cells presented higher levels of some pro-inflammatory molecules (NF-kB and IDO-1 mRNAs, IL-6 and kynurenine) than female cells. Following cortisol exposure, the levels of the pro-inflammatory cytokines, IL-6 and IL-8, were increased in male cells. Conversely, in female cells IL-6 release was unchanged and IL-8 levels were decreased. Anti-inflammatory cytokines, IL-4 and IL-10, did not change in male cells and increased in female cells. Interestingly, kynurenine levels were higher in female cells than in male cells following cortisol stimulus. These results highlighted that cortisol differently affects male and female lymphomonocytes, shifting the cytokine release in favour of a pro-inflammatory pattern in male cells and an anti-inflammatory secretion profile in female cells, opening the way to study the influences of other stressful factors involved in the neurohumoral changes occurring in the response to stress conditions
Human Neural Stem Cell Aging Is Counteracted by α-Glycerylphosphorylethanolamine
No full textNeural stem cells (NSCs) represent a subpopulation of cells, located in specific regions of the adult mammalian brain, with the ability of self-renewing and generating neurons and glia. In aged NSCs, modifications in the amount and composition of membrane proteins/lipids, which lead to a reduction in membrane fluidity and cholinergic activities, have been reported. In this respect, molecules that are effective at normalizing the membrane composition and cholinergic signaling could counteract stem cell aging. α-Glycerylphosphorylethanolamine (GPE), a nootropic drug, plays a role in phospholipid biosynthesis and acetylcholine release. Herein, GPE was assayed on human NSC cultures and on hydroxyurea-aged cells. Using cell counting, colorimetric, and fluorimetric analyses, immunoenzymatic assays, and real time PCR experiments, NSC culture proliferation, senescence, reactive oxygen species, and ADP/ATP levels were assessed. Aged NSCs exhibited cellular senescence, decreased proliferation, and an impairment in mitochondrial metabolism. These changes included a substantial induction in the nuclear factor NF-κB, a key inflammatory mediator. GPE cell treatment significantly protected the redox state and functional integrity of mitochondria, and counteracted senescence and NF-κB activation. In conclusion, our data show the beneficial properties of GPE in this model of stem cell aging
Translocator protein ligands as promising therapeutic tools for anxiety disorders
No full textThe Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is an 18 kDa mitochondrial protein primarily involved in steroid biosynthesis in both peripheral and glial cells. It has been extensively reported that TSPO regulates the rate-limiting translocation of cholesterol from the outer to the inner mitochondrial membrane before its transformation by cytochrome P450scc into pregnenolone, which is further converted into an array of different steroids. In the brain, neurosteroids such as allopregnanolone and pregnenolone, acting as positive modulators of γ-aminobutyric type A (GABAA) receptors, exert anxiolytic activity. Specific ligands targeting TSPO increase neurosteroid production and for this reason they have been suggested to play an important role in anxiety modulation. Unlike benzodiazepines (Bzs), which represent the most common anti-anxiety drugs administered around the world, selective TSPO ligands have shown anxiolytic effects in animal models without any of the side effects associated with Bzs. Therefore, specific TSPO ligands that are able to promote neurosteroidogenesis may represent the future of therapeutic treatment of anxiety disorders. Furthermore, TSPO expression levels are altered in several different psychiatric disorders in which anxiety is the main symptom. This article reviews the primary and patent literature over the last decade concerning the development of novel TSPO ligands that have resulted effective in various models of anxiety, taking into special consideration their structure-activity relationships
Unfractionated and Low Molecular Weight Heparins Differentially Affect the Activation of Serine/Threonine Protein Kinase AKT
No full textCorrelation between lymphocytic peripheral benzodiazepine receptor levels and psychiatric scale scorse in post-traumatic stress disorder and traumatic grief
No full textThe peripheral benzodiazepine receptor (PBR) is a ubiquitary protein which is mainly localized in mitochondria, and plays a pivotal role in the cell homeostasis. Previous studies had evidenced alterations in PBR expression levels during acute or chronic stress states and in many mental diseases. In mitochondrial membranes of lymphocytes isolated from PTSD or CG patients the PBR density has been found decreased with respect to healthy controls (t test: p<0,05).
To assess the relationship between disease-induced PBR levels and the symptoms of PTSD and CG, we evaluated correlations between PBR density and the psychiatric scale scores obtained by patients
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