Ibuprofen treatment ameliorates memory deficits in rats with collagen-induced arthritis by normalizing aberrant MAPK/NF-κB and glutamatergic pathways

Many studies have indicated that the risk of cognitive impairment is higher in patients with rheumatoid arthritis (RA). Additionally, patients with RA may have a lower incidence of cognitive impairment with long-term use of ibuprofen. This study was aimed at investigating the impacts of RA on memory function and the mechanisms that ibuprofen may exhibit to improve memory function in rats with collagen-induced arthritis (CIA). Ibuprofen (30 mg/kg) was given twice daily to CIA rats for two weeks starting from Day 18 following the first immunization. Memory function was measured by the Morris water maze (MWM) test and long-term potentiation (LTP). The proinflammatory cytokine levels and downstream signaling pathways, including mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB), were examined. Furthermore, the glutamatergic system, including glutamate transporters/receptors and brain extracellular levels of glutamate, was investigated. The results showed that the impaired learning memory in CIA rats, examined by the MWM test and LTP, can be ameliorated by ibuprofen treatment. Along with the improvement in memory deficits, ibuprofen attenuated both neuroinflammation and the associated elevated levels of phosphorylated p38, JNK, and p65 in the hippocampus of CIA rats. In addition, the decreased excitatory amino acid transporter 2 level, the increased extracellular glutamate, and the upregulated hippocampal NMDA receptor 2B of CIA rats were all normalized by ibuprofen treatment. These findings suggest that the effect of ibuprofen on the memory improvement in CIA rats is associated with the normalization of the activated MAPK and NF-κB pathways and the aberrant glutamatergic system.