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Inflammation and Vulnerability for Major Depression: in Search of Common Molecular Pathways

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Inflammation and Vulnerability for Major Depression: in Search of Common Molecular Pathways UNIVERSITÀ DEGLI STUDI DI MILANO Dipartimento di Scienze Farmacologiche e Biomolecolari Dottorato in Scienze Farmacologiche Sperimentali e Cliniche XXIX CICLO Inflammation and vulnerability for major depression: in search of common molecular pathways Settore Scientifico-Disciplinare BIO/14 Andrea Carlo Rossetti Matricola: R10664 Tutor: Prof. Raffaella Molteni Coordinatore: Prof. Alberto Corsini Anno Accademico 2015/2016 Abstract The comprehension of the molecular mechanisms underpinning Major Depression (MD) is becoming a crucial issue in public health, considering that this psychiatric disorder has been estimated to become the leading cause of disability within 2020. To sustain the critical relevance of the investigation of the molecular bases of this pathology, it is important to underline that a high percentage of patients do not respond to the current pharmacological treatments, despite the number of antidepressant drugs available in the market. MD is a very complex and invalidating pathology, characterized by neuro-vegetative and cognitive symptoms. Among them, the most relevant are alterations in mood and anhedonia, the latter defined as the incapability of feeling pleasure in pleasant circumstances. Although the causes of MD are not fully understood, it is known that the insurgence of this pathology is ascribable to the interaction between a genetic background of susceptibility and environmental factors. Among these factors, stress exposure play a pivotal role in the development of the psychopathology. However, it is important to mention that not all the subjects exposed to stressful situations develop a mental illness, indeed only a small percentage become affected by MD after stress exposure. In this context, people capable to cope with the consequences of stress are defined as resilient and the term “Stress-Resilience” refers to the ability of the subject to actively respond against adverse stimuli. The investigation and the identification of the molecular mechanisms underpinning stress vulnerability and stress resilience appear, thus, of critical importance to identify new therapeutic targets. Among the molecular mechanisms involved in depression pathophysiology, compelling clinical and preclinical evidence support a role for alteration of the inflammatory system, which is also affected by stressful experiences. With these premises, the general aim of my study was to investigate the relationship between major depression and neuroinflammation, in order to provide new information about the molecular background of this pathology. In particular, by the use of different experimental approaches, we evaluated the impact of stress on neuroinflammation and the potential anti- inflammatory properties of pharmacological treatment with the antidepressants agomelatine and imipramine or the antipsychotic lurasidone. Our results demonstrated that neuroinflammation is strictly associated with the insurgence of stress-induced behavioral alterations in adult male rats tested for sucrose consumption. Indeed anhedonic-like animals showed increased levels of pro-inflammatory cytokines and markers of microglia activation, especially in the dorsal hippocampus. Moreover, we found that chronic pharmacological treatment with agomelatine, imipramine and lurasidone was not only able to normalize the alterations in sucrose intake, but also to modulate the pro- inflammatory effects of chronic stress exposure. In this context, we found that agomelatine was able to modulate the feedback inhibition pathway of interleukin-6 signaling. Indeed, we observed that chronic administration of the antidepressant potentiated the activity of the suppressor of cytokine signaling (SOCS)3 in the prefrontal cortex of stressed animals, thus promoting the shutdown of IL-6 pathway. Subsequently, we used an unbiased genome-wide approach to characterize with a broader point of view the potential protective properties of agomelatine on a strong immune challenge such as the acute injection of lipopolysaccharide (LPS) in the rat ventral hippocampus. In particular, we enlightened molecules and pathways potentially important for its therapeutic effects in the context of neuroinflammation. Pursuing the idea that stress-Resilient animals actively cope with stress-induced alteration/priming of inflammation within the brain, we exposed adult male rats to two weeks of Chronic Mild Stress (CMS), followed by an immune challenge with LPS. Specifically, we found that stress-Resilient rats could better respond to LPS-induced behavioral alterations in sucrose intake. Moreover, our molecular analyses pointed out that dysregulated activation of microglia may play a pivotal role in the insurgence of altered behaviors in anhedonic-like animals, thus indicating these cells as main actors in the mechanisms of stress-Resilience. Lastly, we found that the altered expression of brain-derived neurotrophic factor (BDNF), a key molecule involved in the etiology of MD and in the therapeutic activity of antidepressants, influenced the inflammatory response within the brain. Specifically, we found that male and female mice heterozygous for this neurotrophic factor, differentially respond to an immune challenge with LPS when compared to wild-type animals, with a genotype*LPS interaction dependent on the brain area examined. Summarizing, the data obtained during my PhD strongly support the direct involvement of neuroinflammation in the insurgence of depressive-like phenotype, in the mechanism of stress resilience and in the molecular activity of diverse psychotropic drugs. La comprensione dei meccanismi molecolari alla base della Depressione Maggiore (MD) sta diventando un fattore importante nella salute pubblica, basti considerare che è stato stimato che questa patologia psichiatrica diventerà la seconda causa di disabilità al mondo entro in 2020. A sostegno della criticità dello studio delle basi molecolari della malattia, è importante sottolineare che una alta percentuale di pazienti non risponde correttamente ai trattamenti farmacologici oggi disponibili sul mercato. La MD è una patologia invalidante e altamente complessa, la cui sintomatologia è caratterizzata da sintomi neuro-vegetativi e cognitivi. Tra questi, i più importanti sono l’alterazione del tono dell’umore e l’anedonia, quest’ultima definita come l’incapacità di provare piacere in situazioni che dovrebbero suscitarlo. Nonostante le cause della MD non siano ancora del tutto note, è risaputo che l’insorgenza della patologia è imputabile all’interazione tra un background di suscettibilità genetica e fattori ambientali. Tra questi, l’esposizione a stress gioca un ruolo fondamentale nello sviluppo della psicopatologia. Tuttavia, è importante sottolineare che non tutti i soggetti esposti a situazioni stressanti sviluppano un disturbo mentale, infatti solo una piccola percentuale risulta affetta da MD in seguito all’esposizione a stress. In questo contesto, persone in grado di affrontare positivamente le conseguenze dello stress sono definite resilienti e il termine “Resilienza allo Stress” si riferisce all’abilità di un soggetto di rispondere attivamente e positivamente contro uno stimolo esterno. Lo studio e l’identificazione dei meccanismi molecolari alla base della vulnerabilità allo stress appaiono, dunque, di importanza critica per la scoperta di nuovi target farmacologici. Tra i meccanismi molecolari coinvolti nella patofisiologia della depressione, diversi dati clinici e preclinici supportano il ruolo delle alterazioni a carico del sistema infiammatorio, il quale risulta essere influenzato anche dall’esposizione a situazioni stressanti. Con queste premesse, lo scopo generale del mio studio è stato quello di indagare la relazione tra depressione maggiore e neuroinfiammazione, con il fine di fornire nuove informazioni sul substrato molecolare della patologia. In particolare, attraverso diversi approcci sperimentali, abbiamo valutato l’impatto dello stress sulla neuroinfiammazione e il potenziale effetto anti-infiammatorio del trattamento farmacologico con gli antidepressivi agomelatina e imipramina o l’antipsicotico lurasidone. I nostri risultati hanno dimostrato che la neuroinfiammazione è strettamente associata con l’insorgenza di alterazioni comportamentali indotte dallo stress in ratti maschi adulti, testati con il test del consumo del saccarosio. Infatti, animali con un comportamento simil-anedonico hanno mostrato aumentati livelli di citochine pro-infiammatorie e marcatori di attivazione microgliale, con una specificità particolare per l’ippocampo dorsale. Inoltre, abbiamo mostrato come il trattamento cronico con agomelatina, imipramina e lurasidone non sia stato solo in grado di normalizzare le alterazioni a livello del consumo di saccarosio, ma anche di modulare gli effetti pro-infiammatori dell’esposizione a stress cronico. In questo contesto, è emerso come agomelatina sia in grado di modulare i meccanismi di feedback negativo del pathway dell’interleuchina 6. Infatti, abbiamo osservato che la somministrazione cronica dell’antidepressivo è stata in grado di potenziare l’attività del soppressore del signaling delle citochine (SOCS)3 nella corteccia prefrontale degli animali stressati, promuovendo, quindi, lo spegnimento del pathway di IL-6. Successivamente, abbiamo adottato un approccio genome-wide per caratterizzare -da un punto di vista più ampio- le potenziali proprietà protettive di agomelatina su di un challenge immunologico con lipopolisaccaride (LPS). Nell’ippocampo ventrale di ratto, abbiamo evidenziato diverse
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