Divergent neurobehavioral effects of hydroxychloroquine and leflunomide in a rat model of rheumatoid arthritis.

BACKGROUND

Rheumatoid arthritis (RA) is often associated with neuropsychiatric comorbidities; yet, little is known about the central neurobehavioral fingerprints of disease-modifying antirheumatic medications (DMARDs).

METHODS

Twenty four Adult male rats were divided in to four groups: one negative control group and three rheumatoid arthritis groups; 1st one served as positive control (0.1 complete Freund's adjuvant), 2nd administered hydrochloroquine (100 mg/kg/day, P.O.) and 3rd leflunomide group (10 mg/kg/day, P.O.). Twenty-four hours after last dose manipulation, open field, passive avoidance, Y maze and light dark test were performed to assess motor, long term memory, short term memory and anxiety behavior respectively. Neurotransmitters and TNF-ɑ were estimated in prefrontal cortex, hippocampus and striatum.

RESULTS

CFA-induced arthritis was accompanied by increased anxiety-like traits and impaired locomotor activity. These anxiety-like characteristics were considerably worsened by daily HCQ treatment, which also interfered with both short-term and long-term memory retrieval pathways. On the other hand, LF therapy had a clear anxiolytic effect. The observed cognitive and emotional declines were accompanied by neurochemical and histopathological alterations. These divergent behavioral profiles were strongly correlated with altered central neurochemistry.

CONCLUSION

These findings suggest that while LF treatment is associated with a reduction in anxiety and neuroinflammation brought on by arthritis, HCQ medication may exacerbate central cognitive and emotional vulnerabilities on its own. Our findings highlight the therapeutic necessity of including central neuropsychiatric monitoring into peripheral DMARD selection.