Investigação do pré-condicionamento inflamatório em camundongos submetidos ao estresse agudo e crônico por contenção

Abstract

Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders worldwide, affecting approximately 280 million people and causing around 700,000 suicides per year. This mood disorder is one of the main causes of disability in the world, and may present several clinical characteristics or comorbidities, such as anxiety. MDD is a heterogeneous mood disorder, associated with different etiological factors, such as genetic and/or environmental. However, its pathophysiology has not yet been fully elucidated. It is known that stress is a common factor in practically all theories proposed to explain the pathophysiological mechanisms of MDD, since repeated exposure to stressful stimuli can induce maladaptive and dysfunctional behavioral, emotional and cognitive changes. Furthermore, there is a relationship between MDD, stress and the inflammatory process. Regarding the latter, it is suggested that an immunological imbalance, and, consequently, an inflammatory hyperactivation triggered by stress, may be involved in the pathophysiology of MDD. However, there is still no broad understanding of the impact of the inflammatory process on the risk of developing the disorder. Thus, the objective of this study was to investigate the effects of inflammatory preconditioning (single administration of lipopolysaccharide - LPS) in male Swiss mice subjected to acute restraint stress (ARS) or chronic restraint stress (CRS), called acute and chronic protocol, respectively. The results indicated that, in the acute protocol, inflammatory preconditioning disturbed an expected physiological response after exposure to an acute stressful stimulus. In this protocol, LPS induced behavioral impairments related to demotivation, without inducing depressive- and anxiety-like behaviors. In the chronic protocol, inflammatory preconditioning impaired adaptive mechanisms to repeated exposure to a predictable stressful stimulus, playing an important role in the development of depressive- and anxiety-like behaviors. The behavioral changes induced by LPS administration in the chronic protocol were related to biochemical and molecular changes, indicating an inflammatory and oxidative imbalance, associated with microglia-induced neuroinflammation, astrocyte atrophy and reduction in brain-derived neurotrophic factor (BDNF). Therefore, this study suggests that inflammatory preconditioning disrupts physiological and regulated behavior after an acute stressful stimulus (acute protocol) and potentiates behavioral, biochemical and molecular changes induced by a repeated physical stress protocol (chronic protocol). Through these findings, modulation of the inflammatory process may be a potential therapeutic strategy to reduce the risk of developing depressive and anxious behaviors.