探討雌激素對腦區二十二碳六烯酸含量與空間學習記憶之影響

Effect of Estrogen on Brain Docosahexaenoic Acid Level and Spatial Learning Memory Performance

陳人睿(JEN-JUI CHEN)

指導教授 ： 蘇慧敏

國立臺灣大學/醫學院/生理學研究所/碩士(2007年)

https://doi.org/10.6342/NTU.2007.01660

摘要

性荷爾蒙雌激素（estrogen）與必需脂肪酸二十二碳六烯酸（22:6n-3, DHA）均為影響腦部神經發育生長與維持功能的重要因子，同時也牽涉阿茲海默氏症的預防與治療。臨床研究發現停經後婦女接受雌激素補充療法後，血漿中的DHA濃度也隨之增加；而擁有高濃度雌激素的懷孕婦女，其體內DHA又比一般女性提高許多。本研究主要探討雌激素能否影響各腦區及周邊組織DHA的存取，進而釐清雌激素與DHA之間的關聯性。

研究方法利用缺乏n-3脂肪酸的飼料建立具有不同DHA層次的雌性Spraque-Dawley大鼠，模擬正常人與阿茲海氏症患者體內的DHA濃度。當雌鼠性成熟後，給予卵巢切除手術（ovariectomy）剝奪體內雌激素，一個月後分別補充富含n-3脂肪酸的魚油或安慰劑（水），再利用Morris水迷宮行為實驗測試雌鼠之空間記憶學習能力。動物於犧牲後收集組織進行下列生化分析：(1)脂肪酸分析，檢測包括海馬迴、嗅球、下視丘、肝臟及紅血球中的DHA含量；(2)雌激素濃度量測；(3)雌激素受體α、β（estrogen receptor α、β）於海馬迴之表現情形。

藉由本論文之實驗結果，發現：(1)缺乏DHA之中年雌鼠，藉由卵巢切除手術剝奪體循環之雌激素濃度，可造成腦區與周邊組織之DHA含量的下降，各組織之流失率以紅血球（36%）最高，其次依序為下視丘（35%）、嗅球（33%）、肝臟（31%），平均衰減幅度到達三成左右；(2)食用正常飼料之中年雌鼠，其腦區不因血漿中雌激素濃度之剝奪而下降，但周邊組織則會；(3)缺乏DHA之成年雌鼠，其腦區及周邊組織中的DHA含量不受血漿中雌激素濃度的下降而改變；(4)利用卵巢切除手術剝奪血漿中雌激素濃度，並不影響腦部雌激素濃度；(5)利用卵巢切除手術剝奪血漿中雌激素濃度會降低海馬迴中雌激素β受體（ERβ）的表現量；(6)利用卵巢切除手術剝奪血漿中雌激素濃度可能影響空間學習記憶的表現。
綜合以上所述，本實驗發現正常飲食情況下，個體卵巢切除後僅對周邊組織的DHA含量造成影響，然在飲食缺乏DHA的情況下，個體本身體循環中雌激素的缺乏將會導致中年動物腦區及周邊組織的DHA含量下降，同時，卵巢切除的處理將降低腦部海馬迴雌激素β受體的表現，但不影響腦部雌激素濃度。本研究之結果可增進對於阿茲海默氏症的了解，釐清雌激素與DHA之重要性，對於雌激素補充療法的機轉提供另一種可能的機制─透過影響腦區DHA濃度而達到預防治療之效。

關鍵字

雌激素 ； 二十二碳六烯酸 ； 空間學習記憶 ； 阿茲海默氏症

並列摘要

Background:
Postmenopausal women who take estrogen therapy have higher plasma DHA level and women have higher DHA level in plasma than men, indicating estrogen may play an important role for DHA accumulation in tissues.
Aim:
The study is to determine whether estrogen deprivation could decrease DHA deposition in brain regions and peripheral tissues.
Material and method:
DHA deficient rats were created by feeding DHA deficient diet for one generation. The DHA deficient rats (F2) and the chow diet feeding animal (F1) were ovariectomized (OVX) or sham operation either at age of 60 days old as adult group or at age of 8-12 months old as aging group. Animals were sacrificed 2-3 months after the surgery.
Results:
The DHA level in the brain regions and peripheral tissue of aging F2 was declined after ovariectomy. The loss percentage of DHA compared with the sham operation aging F2 was 36% in erythrocyte, 35% in hypothalamus, 33% in olfactory bulb, 31% in liver. The DHA level in erythrocyte and liver was decreased 25% and 22%, respectively, in the aging F1 after ovariectomy. However, DHA level in the brain regions was not changed. The DHA level in the brain regions and peripheral tissue was not decreased in adult F2 after ovariectomy. Brain estradiol concentration was not reduced after ovariectomy in the aging or the adult groups. However, estrogen receptor β expression in hippocampus was down regulated after ovariectomy in the aging F1 and aging F2 group.
Conclusion:
The DHA level in the brain regions and peripheral tissues was reduced, ERβ expression was down-regulated, but the brain estradiol concentration was not decreased in the aging DHA deficient rats with ovariectomy. It was suggested that circulation estrogen may play a role in brain DHA accumulation.

並列關鍵字

estrogen ； DHA ； spatial learning memory

參考文獻

Behl C (2002) Oestrogen as a neuroprotective hormone. Nature Reviews Neuroscience 3:433-442.

Brinton RD, Chen S, Montoya M, Hsieh D, Minaya J (2000) The estrogen replacement therapy of the Women's Health Initiative promotes the cellular mechanisms of memory and neuronal survival in neurons vulnerable to Alzheimer's disease. Maturitas 34 Suppl 2:S35-52.

Burdge GC (2006) Metabolism of [alpha]-linolenic acid in humans. Prostaglandins, Leukotrienes and Essential Fatty Acids 75:161-168.

Burdge GC, Postle AD (1994) Hepatic phospholipid molecular species in the guinea pig. Adaptations to pregnancy. Lipids 29:259-264.

Burdge GC, Wootton SA (2002) Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. Br J Nutr 88:411-420.