Background/Purpose: Cognitive dysfunction including depression-like symptoms is a frequent comorbidity of rheumatoid arthritis (RA). Recently, rats with adjuvant-induced arthritis (AIA) were found to exhibit reduced levels of brain-derived neurotrophic factor (BDNF), a neurotrophin largely involved in neuroplasticity, learning, memory and cognitive abilities, in cognition-related brain regions¹. Tofacitinib, an inhibitor of JAK3 and JAK1, has a great effect on RA activity, but whether it might improve cognition is unknown. To answer this question, the present study investigated the effect of Tofacitinib on brain BDNF levels and depression-like symptoms in AIA rats.

Methods:

AIA was induced by injection of Mycobacterium butyricum in the tail of male Lewis rats. A group of rats without arthritis served as controls. At the first signs of arthritis, AIA received Tofacitinib (10 mg/kg twice daily, s.c.) or saline (Vehicle). Arthritis score was daily evaluated and a radiographic score was attributed to hind paws at the end of the treatment period. After 21 days of treatment, BDNF levels were measured in two brain regions involved in cognition (prefrontal cortex and hippocampus) using western blot analysis. Anhedonia as a core symptom of depression was assessed from the sugar preference test before and during (3 times) treatment.

Results: As compared to controls, AIA resulted in depression-like symptoms from day 6 to 28 post-immunization. These symptoms coincided with a significant decrease in BDNF levels in the prefrontal cortex (-46%, p< 0.001) but not in the hippocampus (-5%, n.s.). BDNF levels were higher in Tofacitinib-AIA rats than vehicle-AIA rats either in the prefrontal cortex (+20%, p< 0.05) or hippocampus (+132%, p< 0.001). By contrast, anhedonia did not differ between Vehicle- and Tofacitinib-AIA rats.

Conclusion: The present data showed that Tofacitinib increased cerebral BDNF levels in AIA rats whatever the cognition-related structure considered, but with a stronger effect in the hippocampus than in the prefrontal cortex. However, the positive effect of Tofacitinib on BDNF did not translate into reduced anhedonia. Further studies are needed to identify the BDNF-dependent cognitive functions that are improved by Tofacitinib in RA.

¹ Pedard M, Demougeot C, Prati C, Marie C. Brain-derived neurotrophic factor in adjuvant-induced arthritis in rats. Relationship with inflammation and endothelial dysfunction. Progress in Neuropsychopharmacology & Biological Psychiatry, 2018, 82:249-254.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tofacitinib-enhanced-cerebral-brain-derived-neurotrophic-factor-levelsin-a-rat-model-of-rheumatoid-arthritis/