天麻水萃物的抗憂鬱效果

Abstract

憂鬱症是嚴重影響病患本身及其家人、社會的一種精神疾病，會造成嚴重的失能與死亡， WHO預估憂鬱症將在2020年時成為世界第二的高負擔疾病。憂鬱症的罹病率有增高的趨勢，由於藥物的效果不理想、副作用等因素，接受治療的比例卻不到五成。高比例的未治療病患會帶來更高的社會與經濟負擔，因此，開發療效佳且低副作用的替代治療方式，例如具有抗憂鬱效果的傳統草藥，是一個很有潛力且必要的研究。天麻是中國傳統中藥的材料，在食療中常用來鎮靜安神、改善神經衰弱、健腦等。本實驗目的要了解天麻水萃物在動物實驗模式forced-swimming test（FST）的抗憂鬱效果，同時以抑制型逃避學習作業（inhibitory avoidance task, IA）與莫氏水迷津（Morris water maze, WM）來了解天麻水萃物是否能改變大鼠因強迫游泳引起的記憶減退問題，並以細胞實驗來探討天麻水萃物的抗憂鬱機制。實驗結果發現，不論是短期實驗（一天內給予三次天麻水萃物）或是長期實驗（連續21天每天給予一次天麻水萃物），都可以顯著的減少大鼠在FST中的不活動時間，顯示天麻水萃物在此動物模式中具有抗憂鬱的效果；大鼠腦部的單胺類物質含量，在長期實驗中，血清素的含量在天麻高劑量組與正對照組有顯著性增加，而其代謝產物5-hydroxyindoleacetic acid（5-HIAA）含量則顯著性降低，天麻組與正對照組均能降低大腦皮質前側的血清素代謝速率；多巴胺在紋狀體中的含量，不論是在短期或長期實驗中，都能顯著性增加多巴胺含量且減低其代謝產物dihydroxyphenylacetic acid（DOPAC）的含量，對於多巴胺的代謝速率有顯著性降低的作用。在IA與WM學習階段前5分鐘給予大鼠15分鐘的強迫游泳，能顯著降低大鼠在中的記憶能力，若連續給予21天天麻水萃物，則能改變大鼠在IA與WM中，由引起大鼠產生類似憂鬱情緒的強迫游泳而減退的學習記憶能力，推測天麻水萃物能改善憂鬱帶來的記憶減退現象。除了動物實驗中發現天麻具有調節單胺類神經傳導物質，並能降低大鼠腦部與血液中脂質過氧化產物TBARS之能力外，本研究在細胞實驗模式發現經過天麻水萃物48小時處理的PC12細胞，細胞中單胺氧化酶（monoamine oxidase, MAO）的活性，能顯著被抑制；已知的天麻活性成分p-hydroxybenzyl alcohol（HBA）在100 μM與50 μM、vanillin（VAN）在100 μM下對於MAOA有抑制的效果，而4-hydroxybenzaldehyde（HB）在100 μM與HBA在100 μM濃度下對MAOB也具有抑制效果，因單胺氧化酶為代謝單胺類物質5-HT與DA的主要酵素，因此推測HB、HBA與VAN為天麻水萃物中抑制MAO活性主要成分，其中又以HBA效果為佳。未來應針對天麻水萃物抑制天麻水萃物的途徑以及其他可能的抗憂鬱機制進行研究，天麻水萃物中的抗憂鬱活性成分以及最適劑量也應該進一步了解，並進行臨床試驗，使天麻水萃物能應用於臨床上。

Depression is a common psychiatric disease with high morbidity and mortality. It affects not only the patients themselves, but also their family and the society. It imposes a heavy burden on the society and the economics. The World Health Organization (WHO) estimates that major depression is the second greatest single cause of disability worldwide. However, the treatment prevalence rate of depression is less than 50%. The reaons of the low treatment rate may be the undesirable efficacy and the side effects of the medication. Thus, looking for an alternative treatment, such as a traditional medicine, with high antidepressant effect and low side effects is important. Gastrodia elata Bl. is a famous Chinese medicine used for centries. The aims of this study are to examine the antidepressant effects of the water extract of Gastrodia elata Bl. (WGE) using the animal model forced-swimming test (FST) in both acute and subchronic treatments, and to analyze the neurotransmitter concentration in brain regions related to depression. The effects of WGE on learning and memory function of rats in the inhibitaor avoidance task (IA) and Morris water maze (WM) after the forced-swimming procedure was studied. Furthure more, the possible mechanism of WGE as an antidepressant was investigated in in vitro study. The results showed that WGE significantly reduced the immobility time of rats in FST in both acute and subchronic treatments, and the serotonin and dopamine turnover were reduced in rats’ brain after WGE administration. Fifteen mins of forced-swimming procedure (FS), which induced depressive-like affection in rats, administered before the training sessions significantly impair the learning and memory function of rats in the IA and WM. The WGE treatment for consecutive 21 days significantly attenuated dificits in the learning and memory caused by FS. Besides the momoamine modulation and lipid peroxidation inhibition found in the animal models, the inhibition effects of WGE on monoamine oxidase (MAO) activity were studied with PC12 cell line. The results revealed that MAO activity in the PC12 cells incubated with WGE for 48 hr was decreased, but WGE could not directly inhibit MAO activity while interacting with MAO. Ther major known active aomponents of Gastrodia elata Bl., 4-hydroxybenzaldehyde (HB), p-hydroxybenzyl alcohol (HBA) and vanillin (VAN), were also used for MAO activity assay. MAOA and MAOB activity were decreased in HBA (100 μM and 50 μM) and VAN (100 μM) groups and HB (100 μM) and HBA (100 μM) groups, respectively. MAO is the major enzyme that metabolites monoamine neurotransmitters, 5-HT and DA, it is suggested that HB, HBA and VAN might be parts of the antidepressant components in WGE. Further studies, such as the inhibition pathway of WGE on MAO activity, the other possible antidepressant mechanisms of WGE, the major antidepressant components in WGE and the optimal dosage of WGE, should be investigated. All of these studies and clinical study will be useful for further clinical use.