O uso de um selenilindol na busca pela felicidade

Abstract

Depression is the most prevalent psychiatric disorder in the world, affecting approximately 300 million people. The pathophysiology of this disorder has not been fully elucidated, possibly because it is highly heterogenic and multifactorial. However, evidences suggest that a dysfunction in monoaminergic and glutamatergic neurotransmission, hyperactivity of the hypothalamus-pituitary-adrenal axis, inflammation, and oxidative stress are associated with behavioral changes observed in patients. Despite the socioeconomic relevance, 40% of depressed patients do not show symptomatic improvement with the drug treatments available today. Thus, considering the multifactorial nature of depression and the need for more efficient treatments, the importance of looking for multi-target molecules with antidepressant effect becomes clear. Initial studies carried out by our research group reported that the compound 3-[(4-chlorophenyl)selenyl]-1-methyl-1H-indole (CMI) has antioxidant effect and protects mice against the depressive-like behavior induced by inflammation. This hybrid molecule combines the pharmacological effects of the selenium atom with the indole group. Thus, the need for more efficient drugs for depression combined with the promising effects of CMI prompted us to dive into the CMI's ability to reverse depression-like behavior in different animal models. In chapter 1 of this thesis, we deepened our knowledge about the potential of CMI to neutralize inflammation-derived oxidants. In chapter 2, we observed that the CMI reversed the depressive-like behavior in mice subjected to acute restraint stress, while also reversed neuroinflammation and oxidative stress. In chapter 3, we faced the ability of CMI to reverse depressive- and anxiogenic-like behavior induced by acute inflammation, through the modulation of the serotonergic system. In chapter 4, we observed that CMI reversed depressive-like behavior and cognitive impairment in mice with breast tumors, through the modulation of nitro-oxidative stress and neuroinflammation. In chapter 5, we advanced the knowledge about the involvement of the BDNF/mTOR pathway in the antidepressantand anxiolytic-like effect of CMI. In chapter 6, we investigated the ability of CMI to improve the depression-like and ansiogenic-like behavior and cognitive impairment in mice that survived sepsis, through modulation of blood parameters, peripheral oxidative stress, neuroinflammation and central nitro-oxidative stress. Together, our results describe the pharmacological potential of CMI and reinforce the relevance of neuroinflammation and nitro-oxidative stress as targets for the treatment of depression. Thus, we aimed to contribute to the development of a new therapeutic adjuvant capable of improving the quality of life of depressed patients and to collaborate with the science communication to help breaking the stigmatization that depression is a purely mental illness.