Efeitos do baricitinibe sobre a neuroinflamação induzida por lipopolissacarídeo: estudo in vitro em células PC 12 e astrócitos e in vivo em camundongos C57BL/6 fêmeas

Abstract

Mental disorders are syndromes characterized by clinically significant disturbances in cognition, emotional regulation, or behavior. According to the World Health Organization (WHO), approximately 280 million people worldwide are affected by these disorders, with depression being one of the most prevalent conditions. In this context, there is growing interest in understanding the pathophysiological mechanisms involved, such as the neuroinflammation hypothesis, which suggests that inflammatory processes may destabilize the central nervous system (CNS) microenvironment, contributing to cognitive deficits, anxiety disorders, and depression. Among the therapeutic targets under investigation, baricitinib (BARI) stands out—a selective inhibitor of the Janus kinase (JAK) enzyme, which is involved in intracellular signal transduction and the regulation of key cellular processes, including inflammatory responses. Given BARI’s mechanism of action, this study aimed to investigate its effects using in vitro models with PC12 cells and astrocytes, and in vivo models with female C57BL/6 mice subjected to neuroinflammation induced by lipopolysaccharide (LPS).In the in vitro experiments, analyses included MTT reduction assay, cell death, mitochondrial function, measurement of reactive oxygen species (ROS), and quantification of the cytokines IL-1β, IL-6, and TNF-α. In the in vivo experiments, mice received LPS at doses of 0.5 mg/kg or 1 mg/kg for 5 or 10 days, followed by treatment with BARI, fluoxetine, or escitalopram at 10 mg/kg. After the treatments, the animals were evaluated using behavioral tests (open field, hole-board, novel object recognition, forced swim), estrous cycle analysis via vaginal lavage, and cytokine quantification in the hippocampus. The in vitro results demonstrated that baricitinib reduced apoptosis, necrosis, mitochondrial dysfunction, and ROS production, in addition to lowering cytokine levels. However, in the in vivo tests, the drug did not significantly reverse LPS-induced anxiety-like, depressive-like behaviors or cognitive impairment, nor did it alter IL-6 and TNF-α levels in the hippocampus. This may be explained by the estrous cycle stages in which the animals were, such as estrus, metestrus, and diestrus.This study demonstrates that baricitinib exerts significant effects in modulating neuroinflammation in in vitro assays, highlighting its cytoprotective potential. Additionally, it emphasizes the influence of hormonal fluctuations on CNS regulation and their possible association with the behavioral outcomes observed in this study.