非類固醇消炎藥對於神經發炎以及血腦屏障類澱粉蛋白之運輸在類風溼性關節炎大鼠中之影響之探討

Abstract

根據流行病學的發現，類風濕關節炎病人發生阿茲海默症的機率較高，而長期服用非類固醇消炎藥，例如：ibuprofen可降低類風濕關節炎病人中併發阿茲海默症的機率，但是使用naproxen並無此現象。目前，關於類風濕關節炎患者使用非類固醇消炎藥，與阿茲海默症發生率之間之可能原因則尚不明確。因此，本研究利用膠原蛋白誘發關節炎動物模型，口服給予兩種不同之非類固醇消炎藥物：ibuprofen及naproxen，評估其血中藥動特性，並比較及其改善神經發炎與對於血腦屏障運輸β-類澱粉蛋白之影響差異。結果顯示，在藥物動力學方面，ibuprofen或naproxen在關節炎大鼠的血中濃度及其對照組間並無顯著差異。在神經發炎方面，ibuprofen和naproxen皆能顯著減少星狀細胞的活化；但在神經微膠細胞，ibuprofen較能顯著降低其活化之現象，而naproxen則相對無助益。在血腦屏障方面，給予ibuprofen可顯著恢復因RA所降低之ZO-1蛋白表現，但是naproxen對此現象則無改善效果，顯示非類固醇消炎藥對於保護血腦屏障的緊密程度存在不同效果。此外，RA所造成大鼠大腦微血管所表達之β-類澱粉運輸蛋白 (包括RAGE與P-gp) 表現之改變，也顯著因著使用ibuprofen而顯著減緩，然而服用naproxen所造成之影響有限；進一步的實驗結果顯示，β-類澱粉蛋白較容易從周邊進入海馬迴堆積之現象，在給予ibuprofen後顯著下降，naproxen則無明顯改善。綜合上述，我們的研究顯示ibuprofen和naproxen緩解神經發炎之程度不同，對於β-類澱粉蛋白在類風濕關節炎大鼠模型中的血腦屏障運輸之影響亦有差異。

Rheumatoid arthritis (RA) has been associated with the occurrence of Alzheimer’s disease (AD) in epidemiological studies. Long-term administration of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen in patients with RA was associated with a decreased incidence of AD. However, the administration of naproxen was considered less effective in reducing the incidence of AD. The underlying link between NSAIDs treatment and the incidence of AD in RA remains elusive. The present study was aimed to investigate the pharmacokinetics of ibuprofen and naproxen, including their effects on neuroinflammation and BBB transfer of Aβ in CIA rats. As a result, the plasma concentrations of ibuprofen or naproxen were comparable between CIA and control rats. As for neuroinflammation, while both ibuprofen and naproxen reduced astrogliosis, the administration of ibuprofen, but not naproxen, can ameliorate microgliosis. Moreover, the expression of tight junction proteins, zona-occludin (ZO-1), at brain microvessels was also improved by ibuprofen, but not by naproxen. In terms of Aβ-transporting proteins, changes of receptor for advanced glycation end products (RAGE) and P-glycoprotein (P-gp) in CIA rats were reversed by ibuprofen treatment, whereas the effects of naproxen were to a lesser extent. Also, the increased levels of Aβ in the hippocampus of CIA rats were reduced by the treatment with ibuprofen, but not by naproxen. In conclusion, these findings showed the differential effects of ibuprofen and naproxen in alleviating the neuroinflammation and BBB transfer of Aβ in animals with RA.