Inflammation has been increasingly reported in the research focusing on the BD pathophysiology and therapy, both in clinical trials35,36 and animal studies.37 In bipolar patients, inflammatory mediators have been implicated in the disorder, potentially influencing the progression or severity.38,39 For instance, the cytokines whose levels are prone to an increase in BD patients, in comparison to healthy controls, include IL-4, IL-6, IL-10, and TNF-α.40 Additionally, the use of anti-inflammatory drugs as adjunctive therapy to mood stabilizers in the context of bipolar mania has demonstrated promising outcomes.35,37,41 Accordingly, it will be of great interest that a BD animal model, besides mimic the behavioral alterations of the disorder, also recapitulates the inflammatory alterations that may occur in bipolar patients, which highlights the need for further research in this field.
In this regard, the present study sought a better insight into the OUA model of BD, which was recently validated by the paper of Valvassori and coworkers.16 By corroborating data from these authors, the present study demonstrated that OUA administration induces an increase in the number of crossings and rearings seven days after OUA administration in rats, and these alterations are preventable by Li. Additionally, such alterations do not perpetuate until 14 days following the ICV infusions, while the forced swimming test showed a depressive-like behavior (“hopelessness”) in the same animals at this period (also preventable by Li). Therefore, our behavioral findings reinforce the consistency of the OUA administration to model BD, which is a step forward to its validation. Indeed, in bipolar patients, manic episodes last at least seven days, while depressive symptoms are present within 14 days in the same subjects.2 This pattern is accurately represented in the OUA model. Besides the study carried out by Valvassori et al.,16 our findings are similar to data provided by other papers, especially in the context of manic-like behaviors following injection of the Na+/K+-ATPase inhibitor.37,42,43
Moreover, the present study focused on the need to model the pro-inflammatory perspective of BD.10 To this aim, we measured the levels of relevant inflammatory mediators (IL-1β, IL-6, IL-10, and TNFα) 14 days after OUA ICV infusions. In all parameters evaluated, OUA elicited a significant increase, while the Li administration reversed these alterations. Intriguingly, a similar study performed by our research group measuring the same cytokines did not find any alterations in these parameters, except IL-6, whose levels were decreased in the striatum of rats receiving OUA.21 Nonetheless, that paper investigated the OUA effect in an acute context, and here the findings are presented in a subchronic/chronic perspective, with the inclusion of the Li treatment for validation purposes. Data provided by our study mimic the inflammatory pathophysiological alterations reported in patients,44 which reinforces the validity of the model to simulate the pathophysiological aspects of the disorder. Further studies are required to unravel the precise mechanisms underlying these alterations in the inflammatory parameters. One possibility is that OUA can activate neuronal signaling pathways ruling the release of cytokines, such as the nuclear factor kappa B (NF-κB), which is activated by the glycoside according to prior studies.45,46 Also, NF-κB upregulation was detected in bipolar patients, potentially contributing to the pro-inflammatory balance of the disorder.47,48
One potential limitation of the present study is that Na+/K+-ATPase activity was not measured to confirm that OUA effects are related to an inhibition of this enzyme. However, this parameter was not altered by the glycoside in the Valvassori and coworkers’ paper,16 which provided the experimental platform for the present study, although OUA is a well-known inhibitor. That study showed no inhibition on the 14th day after ICV infusion of the drug, time in which were carried out the measurements here. By regarding that the enzyme activity is pivotal for many neuronal roles, a stable decrease in this parameter might generate neurological disturbances,49,50 so that the protein can conform to the high OUA concentration to prevent disruption of its functions. Another possibility is the fact glycoside effect on the Na+/K+-ATPase may be independent on the ion transport activity of the protein; instead, the drug can activate a signaling complex comprising the enzyme, cluster determinant 36 (CD36), and Toll-like receptor 4, subsequently triggering inflammation driven by NF-κB.46
It is worthy to note that experiments from the present study timely mimicked the behavioral alterations of the disorder (face validity), as well as its pathophysiological inflammatory alterations (construct validity). Additionally, Li, a standard drug in BD therapy, was able to mitigate the behavioral and pathophysiological alterations induced in the model (predictive validity), which is the final criterion to validate OUA administration as a BD model.
In summary, OUA elicited a manic-like behavior seven days after its ICV administration, which was followed by depressive-like alterations several days later. Additionally, this drug induced an increase in all measured inflammatory mediators (IL-1β, IL-6, IL-10, and TNFα) 14 days after ICV infusions. Li administration alleviated or reversed all these disturbances in behavior and neurochemistry, indicating that OUA administration is a valid model to study neuroinflammation in the context of BD. Since some cytokines are also significantly altered in bipolar patients, this experimental model might be useful to the screening of drug candidates for the therapy of this condition.
Translational Psychiatry Program (USA) is funded by a grant from the National Institute of Health/National Institute of Mental Health (1R21MH117636-01A1, to JQ). Center of Excellence on Mood Disorders (USA) is funded by the Pat Rutherford Jr. Chair in Psychiatry, John S. Dunn Foundation and Anne and Don Fizer Foundation Endowment for Depression Research. Translational Psychiatry Laboratory (Brazil) is funded by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Apoio à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), and Instituto Cérebro e Mente.