Abstract
Type 1 diabetes mellitus (T1DM) is a chronic disease related to a persistent inflammatory process reaching the central nervous system, which leads to psychiatric comorbidities such as depression and anxiety. The search for new therapeutic agents effective in alleviating the psychiatric condition associated with T1DM becomes critical. Using an animal model of T1DM, we aimed to evaluate the effect of a specific specialized pro-resolving lipid mediator Resolvin D5 (RvD5), in preventing behaviors related to depression and anxiety, investigating its influence on inflammasome in interleukin (IL)-1β in the hippocampus and prefrontal cortex. After experimental T1DM induction with streptozotocin (60 mg/kg, i.p.), these animals were treated for 23 days and randomly divided into 6 subgroups according to the treatment: vehicle (VEH), the antidepressant Fluoxetine (FLX; 10 mg/kg), the nonsteroidal anti-inflammatory Ibuprofen (IBU; 30 mg/kg) or Resolvin D5 (RvD5; 1 3, or 10 ng/animal). As a control group for the experimental-T1DM condition, a group of normoglycemic animals treated with VEH underwent the same behavioral tests: elevated plus maze, open field, and modified forced swimming tests. In the end, hippocampus and prefrontal cortex samples were processed to analyze the pro-inflammatory cytokine IL-1β levels. Our data showed that RvD5 treatment prevented the more pronounced anxious-like and reduced the depressive-like behaviors of experimental-T1DM animals and significantly improved the plasma glucose levels. Additionally, RvD5 treatment prevented the increased level of pro-inflammatory cytokine IL-1β in the hippocampus and prefrontal cortex of experimental-T1DM rats. To conclude, RvD5 presents a preventive therapeutic potential in impairing the development of the emotional complications resulting from T1DM. This potential may be related to its protective profile, as demonstrated in this study by its pro-resolutive action on neuroinflammation in the hippocampus and prefrontal cortex.
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Acknowledgements
We are grateful to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES—FinanceCode 001) and Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq). AP Waltrick is recipient of CAPES fellowships. Prof JM Zanoveli and WA Verri Jr receive CNPq productivity’s grant (process number 303863/2020-0; 307186/2017-2).
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This study was supported by Brazilian grants from Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq; 303863/2020–0; 307186/2017–2) and Programa de Apoio a Grupos de Excelência (PRONEX) grant supported by SETI/Fundação Araucária and MCTI/CNPq, and Governo do Estado do Paraná (grant agreement 014/2017, protocol 46.843), which had no other role in the design of the study, collection and analysis of data, and decision to submit the paper for publication.
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Janaina Menezes Zanoveli, Joice Maria da Cunha and Waldiceu Aparecido Verri Jr were responsible to the study conception and design. Material preparation and data collection were performed by Felipe Fagundes Leão and Ana Paula Farias Waltrick. Statistical analysis was performed by Felipe Fagundes Leão and Janaina Menezes Zanoveli. The first draft of the manuscript was written by Felipe Fagundes Leão, Ana Paula Farias Waltrick, and Janaina Menezes Zanoveli. All authors made suggestions and commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Leão, F.F., Waltrick, A.P.F., Verri, W.A. et al. Resolvin D5 disrupts anxious- and depressive-like behaviors in a type 1 diabetes mellitus animal model. Naunyn-Schmiedeberg's Arch Pharmacol 395, 1269–1282 (2022). https://doi.org/10.1007/s00210-022-02274-8
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DOI: https://doi.org/10.1007/s00210-022-02274-8