Abstract
Anxiety and depression are the most prevalent mental illnesses in the contemporary world. Several animal models have been developed to understand the cellular and molecular mechanisms underlying these disorders and the effect of drugs in modulating the associated behavioral responses. Neuroinflammation has been related to mood disorders. Caffeine is a psychoactive substance that acts as a nonspecific blocker of adenosine receptors. Adenosine receptors are present in neurons and glial cells in different brain areas that are involved in controlling anxiety and depression. However, depending on the context, caffeine can exacerbate or inhibit neuroinflammation and behavioral responses associated with these conditions. This systematic review aimed to evaluate the effects of caffeine and related xanthines on neuroinflammation observed in rodent models of anxiety and depression. A systematic database search (PROSPERO CRD42024517989) returned 17 eligible studies, separated based on the animal model. Most of the analyzed studies revealed that caffeine led to a beneficial effect, mitigating anxiety and depressive-like behaviors and possible cognitive impairments induced by stress. In addition, it also reversed oxidative damage and neuroinflammation by reducing levels of pro-inflammatory cytokines such as IL-1ß, TNF-alpha, and IL-6 and inhibiting glial cell activation. Together, these data reveal a robust effect of caffeine in alleviating symptoms for individuals with these disorders, even though the doses and routes of caffeine administration were highly variable among eligible studies. In addition, they advance the identification of cellular and molecular mechanisms underlying these effects.