부산대학교 도서관

Background: The pathophysiology of cognitive impairment remains unclear, however, several studies have demonstrated that pro-inflammatory cytokines such as Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α) and lipocalin-2 (LCN2) are related with cognitive impairment by activation of microglia and astrocyte in brain. Rheumatoid arthritis (RA) is a representative inflammatory disease; however, the association of pro-inflammatory cytokines and LCN2 with cognitive impairment has seldomly been investigated in RA. Hypothesis and Objective: We hypothesized two theory as follows: 1) peripheral arthritis-induced pro-inflammatory cytokines may cause blood–brain barrier (BBB) leakage and inflammation in hippocampus, which is responsible for cognition, via activation of LCN2, microglia or astrocyte in brain. 2) Treatment of TNF-α may improve not only arthritis but cognitive impairment by inhibiting inflammation. Here, we determined the effect of pro-inflammatory cytokines and LCN2 on cognitive impairment in collagen-induced arthritis (CIA) mouse model. In addition, we studied the effect of TNF-α inhibitor (etanercept) on cognitive impairment.Materials and Methods: We induced CIA mice and randomly divided into three groups: Normal (n=10), CIA group (n=10), CIA/Etanercept group (n=10). We evaluated severity of arthritis using clinical scoring system. Joint inflammation, cartilage damage, and osteoclastic bone resorption has checked by staining with hematoxylin and eosin (H&E) and safranin-O. Level of pro-inflammatory cytokines (TNF-α, and IL-6) and LCN2 checked in mice sera using enzyme-linked immunosorbent assay (ELISA). The expression of pro-inflammatory cytokines and LCN2 in ankle and hippocampus analyzed using real-time PCR. The activation of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1) in hippocampus analyzed using immunohistochemistry (IHC). The inflammatory marker such as high mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), cyclooxygenase-2 (COX-2) and LCN2 evaluated by western blot using hippocampal tissue. Cognitive impairment determined by morris water maze (MWM) test. Results: Compared to normal group, CIA mice showed increased severity of arthritis, inflammation and destruction of joint. In MWM test, CIA mice significantly exhibited increased escape latencies and escape time, reduced the time in the target quadrant, and the number of target zone crossings during five study days compared with normal group. The level of pro-inflammatory cytokines (TNF-α, IL-6) and LCN2 in both sera, ankle tissue and hippocampal tissue was significantly increased. In addition, the expression of Iba-1 and GFAP was increased and the level of inflammatory marker such as HMGB1, COX-2 and LCN2 was increased. We examined whether inhibiting inflammation can mitigate the severity of arthritis and cognitive impairment. Compared to CIA mice, CIA/Etanercept group showed decreased severity of arthritis and joint inflammation. In MWM test, CIA/Etanercept group showed reduced escape latencies and escape time, increased the time in the target quadrant and the number of target zone crossings. The level of pro-inflammatory cytokines and LCN2 significantly decreased in both peripheral tissue and hippocampal tissue. In addition, the expression level of GFAP, Iba-1 and inflammatory markers decreased after treatment of etanercept. The results indicated that inhibition of inflammation may improve cognitive impairment. Conclusion: The results suggest that peripheral arthritis induced inflammation is a possible cause for cognitive impairment by increasing pro-inflammatory cytokines and LCN2 in both peripheral tissue and hippocampal tissue in RA. In addition, we indicate that early anti-inflammatory treatment using etanercept may mitigate or inhibit the progression of cognitive impairment in RA.