睡眠障礙會導致認知功能缺失 (cognitive dysfunction)，其中海馬回神經塑性損傷 (impaired neuronal plasticity of hippocampus) 可能是造成認知功能缺失之潛在分子機制。長壽蛋白 (sirtuin 1, SIRT1) 已被證明在調控神經塑性與代謝平衡上，扮演非常重要的角色。緣此，本研究擬深入探討褪黑激素 (melatonin) 施加是否在睡眠剝奪環境下，具有效保存長壽蛋白活性之顯著功效。睡眠剝奪採用水上轉盤法模式 (disc on water)，大鼠於五天睡眠剝奪期間，分別接受每公斤體重 5、25、50 與 100 毫克 (mg/kg) 之褪黑激素注射。研究分別以細胞色素氧化酵素 (cytochrome oxidase, COX) 組織化學法、長壽蛋白免疫組織化學法暨莫式水迷宮學習法 (Morris water maze) 逐一代表神經塑性於代謝 (metabolic)、生化 (biochemical) 暨行為層次上 (behavioral levels) 之潛在改變。研究結果發現，正常鼠海馬回錐狀細胞層 (pyramidal cell layer) 與顆粒細胞層 (granular cell layer) 皆具有強烈之細胞色素氧化酵素與長壽蛋白反應正向標誌神經元；經睡眠剝奪處理後，海馬回內具細胞色素氧化酵素與長壽蛋白反應正向標誌神經元之數目皆顯著降低，且其染色強度亦明顯呈現趨弱之改變。莫式水迷宮學習法之結果與形態學一致，睡眠剝奪鼠之空間記憶能力測試 (spatial memory test) 皆明顯較正常鼠不足。然經褪黑激素注射後，實驗鼠海馬回內無論細胞色素氧化酵素或長壽蛋白之活性反應皆明顯上升，且其行為上之學習表現亦顯著回復。研究結果顯示，褪黑激素可有效保存長壽蛋白活性，進而達到維持海馬回神經塑性與代謝平衡之優越果效。此一研究成果除證明褪黑激素具良好之神經保護功能外 (neuroprotective effects)，亦提供臨床上使用褪黑激素作為治療因睡眠障礙引致之認知功能缺失一可靠之參考指標。
Sleep disorders cause cognitive dysfunction in which impaired neuronal plasticity in the hippocampus may underline the molecular mechanisms of this deficiency. Since sirtuin 1 (SIRT1) plays an important role in maintaining metabolic homeostasis and neuronal plasticity, the present study is aimed to determine whether melatonin exerts beneficial effects on preserving SIRT1 activation following total sleep deprivation (TSD). TSD was performed by disc on water method for five consecutive days. During this period, animals daily received melatonin at doses of 5, 25, 50 or 100 mg/kg. The cytochrome oxidase (COX) histochemistry, SIRT1 immunohistochemistry together with Morris water maze learning test were performed to examine the metabolic, neurochemical, as well as the behavioral changes in neuronal plasticity, respectively. The results indicate that in normal rats, numerous COX and SIRT1 positive-labeled neurons with strong staining intensities were found in hippocampal pyramidal and granular cell layers. Following TSD, both COX and SIRT1 reactivities were drastically decreased as revealed by reduced staining pattern and labeling frequency. Behavioral data corresponded well with morphological findings in which spatial memory test in water maze was significantly impaired after TSD. However, in rats receiving different doses of melatonin, both COX and SIRT1 expressions were successfully preserved. Considerably better performance on behavioral testing further strengthened the beneficial effects of melatonin. These findings suggest that melatonin may serve as a novel therapeutic strategy directed for preventing the memory deficits resulting from TSD, possibly by effectively preserving the metabolic function and neuronal plasticity engaged in maintaining cognitive activity.
