Elisabetta Maffioletti

Blood microRNA changes in depressed patients during antidepressant treatment

MicroRNAs (miRNAs) are potent modulators of protein expression that play key roles in brain pathways regulating neurogenesis and synaptic plasticity. These small RNAs may be critical for the pathophysiology of mental disorders and may influence the effectiveness of psychotropic drugs. To investigate the possible involvement of miRNAs in the mechanism of action of antidepressants (AD), we conducted a whole-miRNome quantitative analysis with qRT-PCR of the changes in the blood of 10 depressed subjects after 12 weeks of treatment with escitalopram. Thirty miRNAs were differentially expressed after the AD treatment: 28 miRNAs were up-regulated, and 2 miRNAs were strongly down-regulated. miRNA target gene prediction and functional annotation analysis showed that there was a significant enrichment in several pathways associated with neuronal brain function (such as neuroactive ligand-receptor interaction, axon guidance, long-term potentiation and depression), supporting the hypothesis that the differentially regulated miRNAs may be involved in the AD mechanism.

Peripheral whole blood microRNA alterations in major depression and bipolar disorder

Major depression (MD) and bipolar disorder (BD) are severe and potentially life-threating mood disorders whose etiology is to date not completely understood. MicroRNAs (miRNAs) are small non-coding RNAs that regulate protein synthesis post-transcriptionally by base-pairing to target gene mRNAs. Growing evidence indicated that miRNAs might play a key role in the pathogenesis of neuropsychiatric disorders and in the action of psychotropic drugs. On these bases, in this study we evaluated the expression levels of 1733 mature miRNAs annotated in miRBase v.17, through a microarray technique, in the blood of 20 MD and 20 BD patients and 20 healthy controls, in order to identify putative miRNA signatures associated with mood disorders. We found that 5 miRNAs (hsa-let-7a-5p, hsa-let-7d-5p, hsa-let-7f-5p, hsa-miR-24-3p and hsa-miR-425-3p) were specifically altered in MD patients and 5 (hsa-miR-140-3p, hsa-miR-30d-5p, hsa-miR-330-5p, hsa-miR-378a-5p and hsa-miR-21-3p) in BD patients, whereas 2 miRNAs (hsa-miR-330-3p and hsa-miR-345-5p) were dysregulated in both the diseases. The bioinformatic prediction of the genes targeted by the altered miRNAs revealed the possible involvement of neural pathways relevant for psychiatric disorders. In conclusion, the observed results indicate a dysregulation of miRNA blood expression in mood disorders and could indicate new avenues for a better understanding of their pathogenetic mechanisms. The identified alterations may represent potential peripheral biomarkers to be complemented with other clinical and biological features for the improvement of diagnostic accuracy.

Role of allelic variants of FK506-binding protein 51 (FKBP5) gene in the development of anxiety disorders.

Anxiety disorders exhibit remarkably high rates of comorbidity with major depressive disorder (MDD). Mood and anxiety disorders are considered stress‐related diseases. Genetic variations in the co‐chaperone FK506‐binding protein 51, FKBP5, which modulates the function of glucocorticoid receptors, have been associated with an increased risk for the development of posttraumatic stress disorder, but data regarding its role in MDD are controversial. The aims of this study were to clarify the role of the FKBP5 gene in depression and anxiety disorders through a case–control study and an association study with personality traits using the Temperament and Character Inventory (TCI) in healthy subjects.

Association between baseline serum vascular endothelial growth factor levels and response to electroconvulsive therapy.

Several studies have shown that vascular endothelial growth factor (VEGF) is implicated in different neuronal processes involved in major depressive disorder (MDD) and in the mechanisms of action of antidepressants.

Nanomedicine in Psychiatry: New Therapeutic Opportunities from Research on Small RNAs

Preclinical Research

Increased serum levels of sortilin-derived propeptide after electroconvulsive therapy in treatment-resistant depressed patients

Purpose Sortilin-derived propeptide (PE) and its synthetic analog spadin show strong antidepressant activity in rodents and, therefore, could be used as a biomarker to evaluate the clinical efficacy of antidepressant treatments. The aim of this study was to determine whether electroconvulsive therapy (ECT) modulates serum PE concentration in patients with treatment-resistant depression (TRD). Patients and methods Forty-five patients with major depressive disorder, who met the Diagnostic and Statistical Manual of Mental Disorders-IV criteria, were selected for this study. Results We did not observe any difference in the PE levels between TRD patients and controls (z=0.10, P=0.92), but we found a strong significant increase between the PE levels measured just before (T0) and about 1 month (T2) after ECT (z=−2.82, P=0.005). A significant difference between T0 and T2 was observed only in responders (z=−2.59, P=0.01), whereas no effect was found in nonresponders (z=−1.27, P=0.20). Interestingly, we found a significant correlation between the increase in PE levels and decrease in Montgomery -Åsberg Depression Rating Scale scores for the total patient sample (P=0.03). Conclusion This study indicates for the first time that ECT affects serum PE concentration in responders and, therefore, could contribute to the evaluation of the therapy success.

Study of the in vitro modulation exerted by the antidepressant drug escitalopram on the expression of candidate microRNAs and their target genes

ABSTRACT Recent studies indicated a role of microRNAs (miRNAs, small non‐coding RNAs which regulate the expression of target genes by acting on mRNAs) in several neural processes, in the pathogenetic mechanisms of neuropsychiatric diseases and in the action of psychotropic drugs. A modulation induced by the antidepressant drug escitalopram on the expression levels of 30 miRNAs was highlighted in the blood of patients suffering from major depressive disorder. With the aim to investigate the effects of escitalopram in an in vitro model, we performed an analysis of the effects produced by escitalopram on the profiles of the 6 miRNAs found to be more significantly modulated in the above‐mentioned study (miR‐130b, miR‐26a and ‐26b, let‐7f, miR‐770‐5p, miR‐34c‐5p) in human U87 glioblastoma cells. Cells were treated with the drug for 24, 48 and 72 h. The obtained results confirmed a significant increase of let‐7f, both after 48 (p = 0.031) and 72 h (p = 0.022), and of miR‐26a after 48 h (p = 0.032). On the same experimental model, a transcriptome analysis was conducted after 72 h, highlighting a drug‐induced modulation of 1184 protein‐coding genes, 207 of which represent let‐7f targets. Particularly interesting was the downregulation of BCOR, CCND1 and ATR, validated let‐7f targets, which play a key role in the mechanisms of neurogenesis, neuroplasticity and protection from oxidative stress in the brain, indicating that escitalopram could exert downstream effects on gene expression through the regulation of specific miRNAs. HighlightsEscitalopram enhances let‐7f and miR‐26a (microRNAs) levels in cultured neural cells.BCOR, CCND1 and ATR (validated targets of let‐7f) are downregulated by escitalopram.

Effetti biomolecolari del maltrattamento infantile: il ruolo dell’epigenetica e dell’infiammazione

Il maltrattamento durante l’infanzia (MI) e spesso associato a un aumento della vulnerabilita a diverse patologie mentali e fisiche, dal momento che avviene in una fase critica per lo sviluppo del cervello e dell’intero organismo, caratterizzato da una grande plasticita e sensibilita agli stimoli ambientali. Negli ultimi anni, la ricerca biologica si e rivolta sempre di piu allo studio delle alterazioni molecolari legate agli effetti del maltrattamento e degli eventi traumatici nel bambino, svelando il ruolo determinante giocato dalle modificazioni di tipo epigenetico, come la metilazione del DNA, in grado di riprogrammare numerosi geni determinanti per i meccanismi di risposta e resilienza allo stress e per la funzionalita dei sistemi neurotrasmettitoriali. Inoltre e stato dimostrato un coinvolgimento negli effetti deleteri del MI anche di alcuni importanti regolatori dell’espressione genica come i microRNA, insieme all’importanza dei processi infiammatori. Il chiarimento di questi meccanismi e fondamentale per la comprensione delle alterazioni a lungo termine causate dal MI e per lo sviluppo di interventi innovativi rivolti sia alla prevenzione che alla cura.

Defining an immune signature predictive of glioma progression

astrocytic end feet that form, togetherwith the endothelial cells, pericytes and the basal lamina, the blood brain barrier (BBB). The close interaction of these components, which is necessary for maintaining the integrity of the BBB, is still poorly understood. In this study we investigated the time course and structural correlates of BBB-damage in a model of NMO and the impact of astrocyte loss on the breakdown and restoration of the BBB. Using an in vivo model of focal NMO in rats based on injection of a recombinant human anti-AQP4 antibody and complement, we found a prominent opening of the BBB to endogenous albumin, immunoglobulin G and fibrinogen and the exogenousmarkermolecules FITC-albumin and Texas Red Cadaverine at early stages (6 h) of lesion development. The extravasation of these molecules was on protein level accompanied by the loss of the tight junction (TJ)molecule occludin from the blood vessels in the lesions, while the TJ molecules claudin5 and claudin3 were largely preserved. On mRNA level a compensatory upregulation of these TJ molecules was observed at the same time. Interestingly, the BBB integrity was rapidly restored (within 24 h), although astrocyte loss was highest at this time point and occludin was still lacking from the lesion, thus indicating compensatory mechanisms at the BBB independent of astrocyte signaling. In conclusion, there is a prominent breakdown of the BBB in early stages of experimental NMO associated with loss of astrocytes and tight junction molecules. Several hours later, the BBB is restored again, even though astrocytes are still absent from the lesion.