INVOLVEMENT OF OXIDATIVE BALANCE IN THE ETIOLOGY, PATHOPHYSIOLOGY AND TREATMENT OF STRESS-RELATED PSYCHIATRIC DISORDERS

Psychiatric disorders are severe and heterogeneous pathologies affecting an individual’s cognition, emotional regulation and behaviour. In 2019, 1 over 8 people was living with a mental illness, with major depressive disorder (MDD) identified as the leading global cause of disability, and with the spread of COVID-19 there has been a strong increase in the prevalence of MDD, anxiety disorder (AD) and eating disorders (ED). Moreover, the pharmacological treatment of psychopathologies is still largely ineffective and presents several critical aspects, such as the latency of therapeutic effects and the number of non-responder patients. On these bases, it is crucial to study psychiatric disorders to identify new molecular systems involved in their pathophysiology, with the aim to develop novel pharmacological strategies. In this context, to help the diagnosis and treatment of such pathologies, and based on the fact that some features are shared among the different pathologies, the Research Domain Criteria (RDoC) initiative has been launched by the National Institute of Mental Health. Indeed, the aetiology of many different psychiatric disorders relies on the same basis: the interaction between susceptibility genes and environmental stimuli, with the most important one being stress. Of course, it must be considered that not all the subjects exposed to stress will develop a psychopathology, and that not all types of stressors have detrimental effects on the organism. Indeed, acute stressors can be considered a fuel for the brain and body, helping to achieve expected results, however, if the stressors persist for longer periods, are too intense, or the molecular underpinnings of the body response have been primed to a maladaptive response by genetic or environmental backgrounds, the outcome of stress could be pathological. Moreover, although particularly defining for MDD, another common feature among different psychiatric diseases is the symptom of anhedonia, the inability to experience pleasure in situations considered satisfying. These common aspects are exploited by researchers and clinicians to study and understand them. Thus, my PhD project aims to study, at preclinical level, the molecular effects produced by different types of stress. In order to do so, I exploited different types and combination of stressors, such as the Chronic Mild Stress (CMS) model of depression, combined with acute physical (restraint stress) and inflammatory (lipopolysaccharide or LPS) challenges, and the Activity-Based Anorexia (ABA) model of anorexia nervosa, focusing on the involvement of oxidative balance, investigated mainly at mRNA and protein levels in such aspects. The choice of this molecular system relies on the fact that the brain requires a lot of energy -that is a generator of oxidative stress- to support neuronal activity, and on the fact that oxidative stress could act as a bridge between neuroinflammation and the dysregulation in synaptic processes (i.e. neurotransmitter and receptors expression and/or function, signalling pathways), both important players in the neurobiology of psychiatric disorders. Considering the choice of the CMS paradigm, it is important to underline that this model is able to produce two different subpopulations of stressed animals: the vulnerable one, that develops the anhedonic -depressive-like- phenotype and the resilient one that, despite stress exposure, does not, and this has a great translational value and allowed us to study, at molecular level, also the population that is not susceptible to stress exposure. The results of my PhD project revealed that oxidative balance is crucial for the proper stress response. Indeed, stress exposure was able to cause oxidative stress in different areas of the CNS of vulnerable animals, but not of resilient ones. This derangement is accompanied by a malfunctioning of the antioxidant pathway of Nrf2, modulation that is once again specific for vulnerable animals, as opposed to resilient ones that showed an increased activation of the antioxidant system. Moreover, the derangement produced by CMS, are exacerbated after a further acute inflammatory challenge, in response to which stress-vulnerable animals showed even higher levels of oxidative stress. In addition, I also demonstrated a role for the antioxidant machinery in the acute stress-response (through the gene expression analysis of different antioxidant enzymes), and its destabilization in chronically stressed animals. We also found that the pharmacological treatments examined (chronic administrations of antipsychotics blonanserin and lurasidone) were able –at least in part and in an anatomical –specific manner- to prevent the negative effects of chronic stress and to re-establish the proper acute response in stressed animals. Finally, the analyses conducted in the ABA model of anorexia nervosa revealed that also in this case the oxidative balance is affected by the stressful experimental paradigm. Considering the very few information available about this model and about anorexia nervosa patients, we expanded our research also to neuroinflammation, with whom it has a very well-known crosstalk, and to neuroplasticity, an important process that is often impaired in psychiatric conditions. We observed that in this early phase of the pathology there is still an adaptive/compensatory response of the animals and a strong effect of the single components of the paradigm, therefore, future studies are necessary to deeply understand the involvement of the molecular systems considered. The results obtained in this thesis indicates a clear involvement of oxidative balance and other systems related to it in the pathophysiology of psychiatric disorders. Indeed, the anhedonic behavior is characterized by an unbalanced equilibrium between pro- and antioxidant factors, that participates in the impaired ability of those animals to respond to subsequent challenges. The pharmacological treatment is able, at least in part, to re-establish the correct oxidative balance, that might therefore represent an important target to take into consideration to improve the pharmacotherapy of psychiatric disorders, however, more studies are necessary to prove the behavioral and molecular effects of compounds able to act directly on the antioxidant machinery.