Vascular and cerebral benefits of Tofacitinib in rheumatoid arthritis: evidence in rat adjuvant-induced arthritis

Abstract Background: To determine vascular and cerebral effects of Tofacitinib in the adjuvant-induced arthritis (AIA) model in rat.Methods: At the first signs of arthritis (day 10-12 post-immunization), Tofacitinib (10 mg/kg s.c., twice daily) or vehicle were administered for 3 weeks in AIA rats. A group of non AIA served as controls. Body weights and arthritis scores were daily monitored. Anhedonia was explored with the saccharin preference test at day 4 (preclinical), day 11 (early) and day 28 (acute arthritis) post-immunization. At the end of the treatment, aorta, brain and blood were collected for analysis of endothelial function using acetylcholine (Ach)-induced relaxation, brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus (Hip) and prefrontal cortex (PFC), and IL-1β, TNFα, IL-17A plasma levels. Radiographic score of paws was also assessed. Results: As compared to vehicle, Tofacitinib reduced body weight loss, arthritis and radiographic scores (p<0.001) but did not change plasma levels of pro-inflammatory cytokines. Tofacitinib fully prevented AIA-associated reduction in Ach-induced relaxation. As compared to controls, vehicle-treated AIA exhibited low BDNF levels in PFC (p<0.001) and anhedonia at all times examined (p<0.05). Tofacinib did not improve anhedonia, but resulted in elevation of BDNF levels both in PFC (p<0.05) and Hip (p<0.001). A positive correlation was observed between brain BDNF levels and endothelial function (p<0.05).Conclusion: Restoration of normal endothelial function and elevation of brain BDNF levels by Tofacitinib in AIA rats support a positive effect of this new antirheumatic drug on cardiovascular and neuropsychiatric comorbidities of rheumatoid arthritis.