Time-dependent biphasic modulation of human BDNF by antidepressants in neuroblastoma cells

<p>Abstract</p> <p>Background</p> <p>Recent rodent studies reported that antidepressant treatments affect the expression of brain-derived neurotrophic factor (BDNF) mRNA in a way that is dependent on treatment duration, by selective modulation of different BDNF transcripts. However, no data are available for the human BDNF gene. We studied the effect of different antidepressants on BDNF mRNA expression in human neuroblastoma SH-SY5Y cells.</p> <p>Results</p> <p>Cultured cells were treated with the antidepressants fluoxetine, reboxetine and desipramine for different time lengths (6, 24, 48 hours). Expression of total BDNF mRNA was analyzed by reverse transcription PCR and levels of different BDNF transcripts were detected by hemi-nested PCR with specific primers.</p> <p>Short-term treatment (6 hours) with reboxetine or desipramine reduced total BDNF, whereas long-term treatment (48 hours) significantly increased total BDNF mRNA levels. These changes were accounted for by differential regulation of BDNF IV and VIa/b transcripts. Fluoxetine showed no significant effects.</p> <p>Conclusion</p> <p>This is the first study showing biphasic changes in the expression of total and specific BDNF transcripts in human cells following antidepressant treatments. These findings suggest that biphasic induction of BDNF by antidepressants could be a feature common to rodents and humans and encourage the use of SH-SY5Y cells as a tool for investigation of drug effects on human genes.</p

Early raise of BDNF in hippocampus suggests induction of posttranscriptional mechanisms by antidepressants

<p>Abstract</p> <p>Background</p> <p>The neurotrophin BDNF has been implicated in the regulation of neuroplasticity, gene expression, and synaptic function in the adult brain, as well as in the pathophysiology of neuropsychiatric disorders and the mechanism of action of antidepressants. Antidepressant treatments have been shown to increase the expression of BDNF mRNA, although the changes measured were found to be different depending on various factors. A few studies only have measured levels of BDNF protein after antidepressant treatments, and poor correlation was found between mRNA and protein changes. We studied the time course of expression of BDNF mRNA and protein during drug treatments, in order to elucidate the temporal profile of regulation of this effector and whether mRNA and protein levels correlate. Rat groups were treated for 1, 2 or 3 weeks with fluoxetine or reboxetine; in additional groups drug treatment was followed by a washout week (3+1). Total BDNF mRNA was measured by Real Time PCR, pro- and mature BDNF proteins were measured by Western blot.</p> <p>Results</p> <p>We found that mature BDNF protein is induced more rapidly than mRNA, by both drugs in hippocampus (weeks 1–2) and by reboxetine in prefrontal/frontal cortex (week 1). The temporal profile of BDNF protein expression was largely inconsistent with that of mRNA, which followed the protein induction and reached a peak at week 3.</p> <p>Conclusion</p> <p>These results suggest that BDNF protein is rapidly elevated by antidepressant treatments by posttranscriptional mechanisms, and that induction of BDNF mRNA is a slower process.</p

Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways

<p>Abstract</p> <p>Background</p> <p>Agomelatine is a melatonergic receptor agonist and a 5HT_2Creceptor antagonist that has shown antidepressant efficacy. In order to analyze separately the effect of the two receptorial components, rats were chronically treated with agomelatine, melatonin (endogenous melatonergic agonist), or S32006 (5-HT_2Cantagonist), and then subjected to acute footshock-stress.</p> <p>Results</p> <p>Only chronic agomelatine, but not melatonin or S32006, completely prevented the stress-induced increase of glutamate release in the rat prefrontal/frontal cortex.</p> <p>Conclusions</p> <p>These results suggest a potential synergy between melatonergic and serotonergic pathways in the action of agomelatine.</p

Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression.

An animal model of depression combining genetic vulnerability and early-life stress (ELS) was prepared by submitting the Flinders Sensitive Line (FSL) rats to a standard paradigm of maternal separation. We analysed hippocampal synaptic transmission and plasticity in vivo and ionotropic receptors for glutamate in FSL rats, in their controls Flinders Resistant Line (FRL) rats, and in both lines subjected to ELS. A strong inhibition of long-term potentiation (LTP) and lower synaptic expression of NR1 subunit of the NMDA receptor were found in FSL rats. Remarkably, ELS induced a remodelling of synaptic plasticity only in FSL rats, reducing inhibition of LTP; this was accompanied by marked increase of synaptic NR1 subunit and GluR2/3 subunits of AMPA receptors. Chronic treatment with escitalopram inhibited LTP in FRL rats, but this effect was attenuated by prior ELS. The present results suggest that early gene-environment interactions cause lifelong synaptic changes affecting functional and molecular aspects of plasticity, partly reversed by antidepressant treatments

Residual tumor micro-foci and overwhelming regulatory T lymphocyte infiltration are the causes of bladder cancer recurrence

Bladder cancer has an unexplained, high recurrence rate. Causes of recurrence might include the presence of sporadic tumor micro-foci in the residual urothelial tissue after surgery associated with an inverted ratio between intratumoral effector and regulatory T cell subsets. Hence, surgical specimens of both tumors and autologous, macroscopically/histologically free-of-tumor tissues were collected from 28 and 20 patients affected by bladder or renal cancer, respectively. The frequencies of effector (IFN?+ and IL17+ T cells) and regulatory (CD4+CD25hiCD127lo and CD8+CD28-CD127loCD39+ Treg) T cell subpopulations among tumor infiltrating lymphocytes were analyzed by immunofluorescence, while the gene expression of MAGE-A1 and MAGE-A2 tumor-associated antigens was studied by RT-PCR. The results show that both the T cell infiltrate and the frequency of MAGE-A1/A2 gene expression were comparable in tumors and in autologous free-of-tumor tissues in bladder cancer, while the autologous free-of-tumor renal tissues showed reduced T cell infiltrate and frequency of MAGE gene expression as compared to the autologous tumors. Importantly, the intra-tumor T effector/Treg cell ratio was consistently &lt;1 in bladder cancer patients (n. 7) who relapsed within two years, while it was always &gt;1 in patients (n. 6) without recurrence (regardless of tumor stage) (P = 0.0006, Odds ratio = 195). These unprecedented findings clarify the pathogenic mechanism of bladder cancer recurrence and suggest that microscopically undetectable micro-foci of tumor may predispose to recurrence when associated with an inverted intratumoral T effector/Treg cell ratio

AIRE polymorphism, melanoma antigen-specific T cell immunity, and susceptibility to melanoma

AIRE is involved in susceptibility to melanoma perhaps regulating T cell immunity against melanoma antigens (MA). To address this issue, AIRE and MAGEB2 expressions were measured by real time PCR in medullary thymic epithelial cells (mTECs) from two strains of C57BL/6 mice bearing either T or C allelic variant of the rs1800522 AIRE SNP. Moreover, the extent of apoptosis induced by mTECs in MAGEB2-specific T cells and the susceptibility to in vivo melanoma B16F10 cell challenge were compared in the two mouse strains. The C allelic variant, protective in humans against melanoma, induced lower AIRE and MAGEB2 expression in C57BL/6 mouse mTECs than the T allele. Moreover, mTECs expressing the C allelic variant induced lower extent of apoptosis in MAGEB2-specific syngeneic T cells than mTECs bearing the T allelic variant (p < 0.05). Vaccination against MAGEB2 induced higher frequency of MAGEB2-specific CTL and exerted higher protective effect against melanoma development in mice bearing the CC AIRE genotype than in those bearing the TT one (p < 0.05). These findings show that allelic variants of one AIRE SNP may differentially shape the MA-specific T cell repertoire potentially influencing susceptibility to melanoma

Lost in translation. New unexplored avenues for neuropsychopharmacology: epigenetics and microRNAs

Introduction: Mood and anxiety disorders are among the major causes of disability worldwide. Despite clear need for better therapies, efforts to develop novel drugs have been relatively unsuccessful. One major reason is lack of translation into neuropsychopharmacology of the impressive recent array of knowledge accrued by clinical and preclinical researches on the brain. Here focus is on epigenetics mechanisms, including microRNAs, which seem particularly promising for the identification of new targets for alternative pharmacological approaches. Areas covered: First, the current knowledge about epigenetic mechanisms, including DNA methylation, posttranslational modification of histone proteins, focusing on histone methylation and acetylation, and posttranscriptional modulation of gene expression by microRNAs is described. Then evidence showing involvement of epigenetics and microRNAs in the pathophysiology of mood and anxiety disorders as well as evidence showing that some of the currently employed antidepressants and mood stabilizers also affect epigenetic and microRNA mechanisms are reviewed. Finally current evidence and novel approaches in favor of drugs regulating epigenetic and microRNA mechanisms as potential therapeutics for these disorders are discussed. Expert opinion: Although still in its infancy, research investigating the effects of pharmacological modulation of epigenetic and microRNA mechanisms in neuropsychiatric disorders continues to provide encouraging findings, suggesting new avenues for treatment of mood and anxiety disorders

Blues in the Brain and Beyond: Molecular Bases of Major Depressive Disorder and Relative Pharmacological and Non-Pharmacological Treatments

Despite the extensive research conducted in recent decades, the molecular mechanisms underlying major depressive disorder (MDD) and relative evidence-based treatments remain unclear. Various hypotheses have been successively proposed, involving different biological systems. This narrative review aims to critically illustrate the main pathogenic hypotheses of MDD, ranging from the historical ones based on the monoaminergic and neurotrophic theories, through the subsequent neurodevelopmental, glutamatergic, GABAergic, inflammatory/immune and endocrine explanations, until the most recent evidence postulating a role for fatty acids and the gut microbiota. Moreover, the molecular effects of established both pharmacological and non-pharmacological approaches for MDD are also reviewed. Overall, the existing literature indicates that the molecular mechanisms described in the context of these different hypotheses, rather than representing alternative ones to each other, are likely to contribute together, often with reciprocal interactions, to the development of MDD and to the effectiveness of treatments, and points at the need for further research efforts in this field

Psicofarmacologia clinica

Il volume raccoglie le acquisizioni più recenti sull'utilizzo clinico delle principali classi di psicofarmaci impiegati nella terapia delle patologie psichiatriche di più rilevante intersse sociale. Si divide in due sezioni principali: le classi di farmaci psichiatrici e i trattamenti psicofarmacologici. Nella Sezione I, per ogni molecola all'interno di una specifica classe, sono commentati i dati di studi preclinici e in fase clinica; inoltre, sono illustrati gli aspetti farmacodinamici e farmacocinetici, le indicazioni terapeutiche, i dosaggi, gli effetti collaterali e le interazioni con altri farmaci, psichiatrici e non psichiatrici. La Sezione II presenta lo stato dell'arte della terapia farmacologica nelle principali malattie psichiatriche. Gli autori descrivono, inoltre, la farmacoterapia in speciali popolazioni, come i bambini e gli adolescenti, i pazienti affetti da malattie sistemiche e gli anziani. Alcuni capitoli son infine dedicati alla psicofarmacoterapia in situazioni particolari, quali la gravidanza, l'allattamento e le emergenze. Particolare cura è stata posta nelladattare la descrizione delle singole molecole alla realtà italiana: sono stati inseriti alcini farmaci non in commercio negli Stati Uniti ma venduti in Italia; inoltre, laddove la legislazione del nostro Paese differisce da quella americana, si è provveduto a fornire indicazioni di sicuro riferimento per lo specialista italiano. Questo volume è una preziosa fonte di informazioni per psichatri, psicofarmacologi, neurologi, geriatri e specializzandi, nonché un valido strumento di approfondimento per gli studenti delle Facoltà di Medicina e Farmacia