Felodipine減緩高膽固醇血症與停經狀態下 根尖病變的惡化

Abstract

根尖病變主要是由於牙髓腔的細菌感染所引起的根尖周圍組織發炎反應，宿主組織在修復時會產生抑制和刺激訊號的複雜交互作用，影響根尖病變的病程發展。 27-羥基膽固醇(27-hydroxycholesterol, 27-HC)是人體內含量最高的羥基膽固醇，也是一種內生性的選擇性雌激素受體調節劑，在停經和高膽固醇血症引起的發炎反應中扮演關鍵角色。我們以巨噬細胞株的實驗證實：當鈣離子濃度改變下，原本存在於細胞質中的類固醇生成急性調控蛋白(steroidogenic acute regulatory protein, StAR)會轉移到粒線體外膜上，使膽固醇能夠進入粒線體基質，與固醇27-羥化酶(CYP27A1)作用生成27-HC。 長期用於治療高血壓的felodipine，經研究證實可以抑制CYP27A1這個酵素。而作為一種鈣離子通道阻斷劑，我們以巨噬細胞株的實驗驗證：felodipine透過抑制鈣離子通道，影響細胞內鈣離子的濃度和轉移，減少StAR蛋白從細胞質轉移到粒線體外膜的量，進而降低膽固醇進入粒線體內部，最後使27-HC生成量下降。使用大鼠作為研究動物的實驗，分成有服用felodipine與對照組的組別，對於有使用felodipine的組別，根尖病變的發炎狀況有改善。結果顯示felodipine應用於臨床上的潛能，也許可以做成奈米藥物後注射至發炎的位置，來達成抑制發炎的效果，同時也比較不會產生全身性的影響。

Periapical lesion is an inflammatory reaction in the periapical tissue caused by the bacterial infection in the pulp chamber. Complex inhibitory and stimulatory signals of the host during the healing process affect the progression of the periapical lesion. 27-hydroxycholesterol (27-HC) are the most abundant oxysterol in humans and an endogenous selective estrogen receptor modulator (SERM), playing a key role in the inflammatory response induced by menopause and hypercholesterolemia. According to our experiments with macrophage cell lines, it has confirmed that when the calcium ion concentration changes, the steroidogenic acute regulatory protein (StAR) originally present in the cytoplasm translocates to outer membrane of mitochondria. After the cholesterol enters the mitochondrial matrix, it interacts with the sterol 27-hydroxylase (CYP27A1) to produce 27-HC. Felodipine, a long-standing drug for treating hypertension, has been shown to inhibit the enzyme CYP27A1. As a calcium channel blocker, our in vitro experiments with macrophage cell lines have verified that felodipine, by block the entry of the extracellular calcium ions, reduces the translocation of StAR protein from cytoplasm to the outer membrane of the mitochondria. Therefore, it decreases the movement of cholesterol into the mitochondria and ultimately reduces the production of 27-HC. In our animal study with rats, the inflammation of the periapical lesion improved in the felodipine-treated group compared with the control group. Perhaps in the form of a nanoparticle drug injected into the site of inflammation, felodipine might achieve an anti-inflammatory effect without causing systemic effects.