台灣土肉桂葉精油及其活性成分枷羅木醇及肉桂醛在小鼠之抗高尿酸血症作用

已知台灣土肉桂葉精油（TC）中主要成分－肉桂醛（cinnamaldehyde）可降低oxonate誘發之高尿酸血症小鼠血清中尿酸濃度。本研究之目的為觀察TC及其成分枷羅木醇和肉桂醛對於預防急性高尿酸血症及治療慢性高尿酸血症引起之血糖異常及發炎作用之影響。第一部分，慢性模式：以 C57BL/6雄性小鼠連續四週腹腔注射尿酸（250 mg/kg /日），正常控制組小鼠則注射等體積之載劑，然後高尿酸血症小鼠連續七日每日灌食 TC（13 mg/kg）、枷羅木醇（2.6、5.2 mg/kg）、肉桂醛（0.4、0.9 mg/kg），或灌食載劑玉米油（4 ml/kg BW），正常控制組小鼠則灌食載劑（4 ml/kg BW），最後一次灌食結束經隔夜空腹後犧牲。第二部分，急性模式：以 C57BL/6雄性小鼠灌食：枷羅木醇（2.6、5.2、10.4 mg/ kg BW）、肉桂醛（0.4、0.9、1.8 mg/ kg BW），或載劑玉米油（4 ml/kg BW），正常控制組小鼠則灌食載劑（4 ml/kg BW），採隔日灌食且共灌食8次。最後一次灌食結束，經隔夜禁食後腹腔注射potassium oxonate（375 mg/kg BW，OX），誘發急性高尿酸血症，正常控制組小鼠則自腹腔注射載劑（10 ml/kg BW），腹腔注射一小時後犧牲。不論急性或慢性模式小鼠均以二氧化碳窒息法犧牲，收集血液及臟器，分析血液生化值及臟器發炎指數。第一部分，慢性模式結果顯示：灌食不同劑量的枷羅木醇、肉桂醛和 TC可降低血尿酸值並改善高尿酸血症小鼠的代謝狀況、空腹高血糖及 HOMA-IR指數。抗發炎方面， TC及其成分可降低血液、腎臟、胰臟及心臟中 nitrate/nitrite和 IL-1β之含量。腎功能方面，灌食不同劑量的枷羅木醇、肉桂醛和 TC均可改善高尿酸血症小鼠 GFR之上升。TC及其成分在腎臟、胰臟及心臟之抗發炎作用與降低NLRP3、ASC、caspase-1及 TLR4、MyD88、MD2表現量有關。第二部分，急性模式結果顯示：灌食不同劑量的枷羅木醇、肉桂醛可預防 OX誘發之血尿酸上升，改善高尿酸血症小鼠的空腹高血糖及 HOMA-IR指數，並降低腎臟、胰臟及心臟中 nitrate/nitrite和 IL-1β之含量。由本研究結果得知，TC及其組成分枷羅木醇和肉桂醛不論在預防或治療高尿酸血症相關的血糖代謝或組織發炎性損傷問題均有相當大的應用潛力。

It has been shown that the leave essential oil of Cinnamomum osmophloeum Kanehira (TC) and cinnamaldehyde, an bioactive composition of TC, reduced serum uric acid concentration in oxonate-induced hyperuricemia in mice. The aim of present study is to investigate the effect of TC and two of its compositions, linalool and cinnamaldehyde, on hyperuricemia-associated hyperglycemic and inflammatory condition in chronic and in acute hyperuricemia in mice. In study part I, male C57BL/6 mice were induced to be chronic hyperuricemia by the injection of uric acid (250 mg/kg BW/day, i.p.) for 4 consecutive weeks followed by receiving 7 consecutive days by gavage TC (13 mg/kg BW), Lin (2.6, 5.2 mg/kg BW), Cin (0.4, 0.9 mg/kg BW) or the vehicle (corn oil, 4 ml/kg BW). Normal control mice injected with an equal volume of vehicle received 7 consecutive days by gavage corn oil. Mice were then sacrificed by CO2 at 24 h after the final intervention. In study part II, male C57BL/6 mice received every other day for eight times by gavage Lin (2.6、5.2、10.4 mg / kg BW), Cin (0.4, 0.9, 1.8 mg/kg BW) or the vehicle (corn oil, 4 ml / kg BW) followed by the injection of potassium oxonate (375 mg / kg BW, OX, i.p.) to induce acute hyperuricemia. Normal control mice that received corn oil were injected with vehicle (10 ml/kg BW). Mice were then sacrificed by CO2 at one hour after the induction. The results of study part I showed that the intervention of all tested doses of Lin, Cin, and TC reduced the serum uric acid concentration and improved the metabolic condition, fasting blood glucose level, and HOMA-IR value in mice. In addition, Lin, Cin, and TC also reduced levels of nitrate/nitrite and IL-1β in kidney, pancreas and heart of these animals. As a result, renal function reflected by GFR was normalized by the intervention with Lin, Cin, and TC which is associated with normalized levels of the expression of NLRP3, ASC, caspase-1, TLR4, MyD88, and MD2 in hyperuricemia mice. The results of study part II showed that OX-induced elevation of blood uric acid level was prevented by Lin and Cin. Similarly, these two compounds reversed acute hyperuricemia-associated elevation of fasting blood glucose level and HOMA-IR value. In addition, Lin and Cin also prevented OX-induced elevation of levels of nitrate/nitrite and IL-1β in kidney, pancreas and heart in mice. In summary, Lin, Cin and TC showed prophylactic and therapeutic effect on acute- and chronic hyperuricemia-associated hyperglycemic and inflammatory condition, respectively, in mice.