Avaliação do efeito antidepressivo e ansiolítico de extrato de Psilocybe cubensis em um modelo de neuroinflamação em camundongos

Abstract

Depression is a common, recurrent disorder and one of the leading causes of disability worldwide. It is a complex condition that frequently coexists with other psychiatric disorders, such as anxiety. In Brazil, it is estimated that approximately 6% of the population has depression, while the prevalence of anxiety is 27%. Despite available treatments, about 30% of patients with depressive disorders do not respond adequately to existing antidepressants, which present limitations such as side effects and unsatisfactory efficacy. Therefore, the search for more effective therapies is necessary. The neurogenesis of these disorders remains poorly elucidated, and recent studies reinforce the theory of neuroinflammation as a possible mechanism involved in their etiology. In parallel, the mechanisms of action of psychedelic drugs, such as psilocybin, are also not fully understood, although recent clinical evidence demonstrates their therapeutic potential. This scenario encourages preclinical investigations to better understand the action of these substances. The aim of this study was to investigate the potential antidepressant and anxiolytic activity of an extract containing psilocybin and its possible antineuroinflammatory action in a preclinical model of neuroinflammation. For this purpose, a lyophilized extract of Psilocybe cubensis was obtained. Male C57BL/6 mice were treated with lipopolysaccharide (LPS, 0.5 mg/kg) for ten consecutive days. One hour after the last dose of LPS, the extract (40 mg/kg or 100 mg/kg), saline solution (0.9%), or escitalopram (10 mg/kg) was administered. The animals were subjected to behavioral tests: forced swim and sucrose splash tests (depression), open field (locomotion), elevated plus maze, and hole-board test (anxiety). Subsequently, the animals were euthanized for hippocampus and prefrontal cortex collection for neurochemical evaluations. The results showed that the extract contained the alkaloids of interest and that LPS induced depressive- and anxiety-like behavior in most tests. The lower dose of the extract partially reversed these effects in some tests, as evidenced by reduced latency time and increased grooming in the sucrose splash test, as well as improvements in exploratory and anxiety-related parameters in the hole-board test. In neurochemical analyses, LPS increased inflammatory markers, with no reversal by the treatments. These findings suggest that the P. cubensis extract may contribute to the treatment of neuropsychiatric disorders and highlight the importance of future studies to elucidate its mechanisms of action in the context of neuroinflammation.