摘 要
環境壓力的因素對於發炎性疾病（如牙周炎）的進展與嚴重程度，扮演著關鍵的角色，並且已被指出對牙周病治療結果有負面的影響。睡眠不足是其中一個壓力因子，它會調節已經建立的牙周病病理生理學的過程，並透過激活下視丘-垂體-腎上腺（HPA）軸來加速牙周組織的降解。由於褪黑激素可以與HPA軸相互作用，因此可以逆轉睡眠障礙等壓力因素造成的影響，成為牙周炎的潛在治療方法。以改良的多平台法（MMPM）為模型，誘導患有或不患有實驗性牙周炎的四組雄性 Wistar大鼠，進行 7 天的睡眠剝奪，其中一組在睡眠剝奪後，給予褪黑激素治療。而HPA 軸對於大鼠應對壓力反應（睡眠剝奪）的影響將通過評估海馬迴和其他大腦區域的皮質酮和糖皮質激素受體（GR）的水平來驗證。慢性不可預測壓力模型和穿梭箱試驗將用於決定褪黑激素給藥是否可以減輕或逆轉大鼠受到壓力引起的行為缺陷。此外，會利用微型電腦斷層掃描及組織切片測量來分析齒槽骨破壞、發炎細胞浸潤至牙周組織、及牙周附連喪失的情形。另外也會收集被絲線綑綁住的臼齒周圍的黏膜牙齦組織，進行骨髓過氧化酶 （MPO） 和 RT-PCR 分析，以確定發炎的病理機制，並評估特定發炎調控介質的基因表達，如TNF-α （腫瘤壞死因子α）、IL-1β（介白素-1 β）、COX2（環氧化酶）和PGE2（前列腺素E2）。透過免疫組織化學染色（IHC）和抗酒石酸酸性磷酸酶（TRAP）染色，可以發現被固定住的大臼齒的牙周組織會表現出多種發炎和成骨的調節因子：TNF-α（腫瘤壞死因子）, IL-1（白血球介素因子1）, RANKL（破骨細胞分化因子）和OPG（破骨細胞抑制因子）。 因此，我們可以假設：利用褪黑激素調解下視丘-腦下垂體-腎上腺軸（HPA axis）具有治療和壓力因素有關的牙周疾病的潛力。
關鍵詞：褪黑激素、壓力、HPA軸、牙周病、皮質醇
Abstract
Environmental stress factors play a pivotal role in the development and progression of inflammatory diseases, such as periodontitis, and have been suggested to have negative influence on the outcome of periodontal treatment. Poor sleep quality is one of such stress factors, which may modulate the pathophysiological processes of the already established periodontal inflammation and accelerate the degradation of periodontal tissues through activating the hypothalamic-pituitary-adrenal (HPA) axis. As melatonin could interact with HPA axis, it may reverse the effects caused by stress factors, such as sleep disturbance, and become a potential treatment for periodontitis. The modified multiple platform method (MMPM) will be used as a model to induce sleep deprivation to four groups of male Wistar rats with or without experimental periodontitis for seven days, and treatment with melatonin will be given to one group following sleep deprivation. The effect of the HPA axis on the rats in response to stress (sleep-deprivation) will be validated by evaluating corticosterone and glucocorticoid receptor (GR) levels in the hippocampus and other brain regions. Chronic unpredictable stress model and shuttle-box test will be used to determine whether melatonin administration can alleviate or reverse the stress-induced behavior deficit in rats. Moreover, alveolar bone destruction, inflammatory cell infiltrate in periodontal connective tissue, and attachment loss will be analyzed by microcomputer tomography and histometric measurements. The mucogingival tissues surrounding the ligatured molars will also be collected for myeloperoxidase (MPO) and RT-PCR analysis to determine inflammatory pathologies and to evaluate the gene expression of specific inflammatory mediators, such as Tumor Necrosis Factor-α (TNF-a), interleukin-1β (IL-1b), Cyclooxygenase-2 (COX2) and Prostaglandin E2 (PGE2). Differential expression profiles of the inflammatory and osteogenic mediators of periodontal tissue surrounding ligatured molars, such as TNF-a, IL-1b, the receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG), will also be observed through immunohistochemical (IHC) staining and Tartrate-resistant acid phosphatase (TRAP) staining. Thus, we hypothesize that melatonin could be a potential therapeutic agent for modulating periodontal disease aggravated by stress factors through alteration of the HPA axis.
Keywords: Melatonin, Stress, HPA Axis, Periodontal Disease, Cortisol