Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/52487
標題: 性荷爾蒙補充物能否恢復大鼠因性腺功能不足而造成中樞神經細胞變化之探討
An Investigation of Whether Gonadal Hormone Replacement Rescues the Changes of Central Neurons in Hypogonadal Rats
作者: 陳建榮
曾國藩
關鍵字: 商品化
aging
基礎醫學類, 藥學
老化
脫氫異雄固酮(DHEA)
海馬回
細胞內染料注射
植物性雌激素
體感覺運動皮質
DHEA
hippocampus
intracellular dye injection
phytoestrogen
sensorimotor cortex
摘要: 生物體中樞神經細胞的樹突會因內、外因素而改變,研究顯示性荷爾蒙能改變腦神經元的型態,影響心智、情緒、精神和認知等。我們近來的研究顯示母鼠感覺運動皮質與海馬回CA1 錐體細胞的樹突會隨著動情週期而變化;摘除卵巢也會改變樹突,補充雌激素則明顯恢復,同時我們也發現老化造成母鼠感覺運動皮質錐體細胞樹突萎縮及樹突棘密度減少,顯示性荷爾蒙能維護中樞神經細胞樹突型態。老化是當前社會的大課題,老化引起的性荷爾蒙缺乏常引發臨床問題,然而性荷爾蒙療法卻有引發腫瘤的風險,因此,找尋替代藥品是刻不容緩的議題。本研究將以我們近來的結果為基礎,以摘除性腺來模擬老化動物以及最後以正常老化動物為對象,藉由型態及電生理方法探討性荷爾蒙缺乏可能引發腦的變化, 再給予天然的植物性雌激素或合成的脫氫異雄固酮(dehydroepiandrosterone, DHEA),檢測其效用。計畫第一年擬以卵巢摘除2 週及8 週後的母大白鼠來分別模擬雌性動物短期及長期缺乏性荷爾蒙,再給予純化的大豆異黃酮(genistein)或DHEA 處理,以水迷宮測試來評估母鼠空間學習能力,同時以細胞內染料注射探討其感覺運動皮質內第三及第五層與海馬回CA1 及CA3 錐體神經細胞的型態變化;再以電泳法分析皮質及海馬回中PSD95, synaptophysin, synaptobrevin 及spinophilin等突觸相關蛋白的相對變化。第二年則探討雄性荷爾蒙對雄性大鼠感覺運動皮質與海馬回細胞樹突的調控,探討睪丸摘除以及外加睪固酮或DHEA 的恢復情形,同時也分析細胞膜電生理特性的變化,以及相關突觸蛋白是否跟著變化,以確認型態學變化的意義。第三年則以自然老化的大鼠為對象,以陰道抹片及血液性荷爾蒙濃度檢查確認無動情週期,再給予genistein 或DHEA,探討這兩種物質是否能提升正常停經後雌鼠的空間學習能力,恢復樹突型態變化。本計劃的結果除能增進我們瞭解性荷爾蒙對感覺運動皮質及海馬回細胞形態及功能的影響外,更可作為例如在老化後性荷爾蒙功能低下時,治療或荷爾蒙補充食品開發之參考。
Adult central neurons alter their dendrites in response to internal and external influences.Studies showed that sex hormone modulates brain neuronal morphology and affects functionsincluding mental state, emotion, psychological status and recognition. Our recent studiesrevealed that primary sensorimotor cortical and hippocampal CA1 pyramidal neurons alteredtheir dendrites cyclically during estrous cycle. In addition, ovariectomy downgraded thedendrites of these neurons and exogenous estrogen restored it satisfactorily. These argue thatgonadal hormone plays significant role in regulating the dendritic structures of centralneurons and cortical functions. Aging, an issue of modern society, compounds individualswith reduced gonadal hormone production and in some dramatic functional degradation. Drugemulates gonadal hormone without risking tumorigenesis- a drawback of hormonal therapy, iseagerly awaited. Here we propose to study the effect of phytoestrogen or DHEA treatment ongonadectomized rats, a surgical model of hypogonadism mimicking aging, and normal agingrats. We focus on morphological and membrane electrical properties of layer III and Vcortical and hippocampal CA1 and CA3 pyramidal neurons. In the first year, we will studythe effect of short and long-term hypogonadism in female by examining rats ovariectomizedfor 2 and 8 weeks and their responses to genistein and DHEA treatments. Spatial memory willbe assessed with Morris water maze, dendritic changes studied following intracellular dyeinjection and changes of synaptic markers including PSD95, synaptophysin, synaptobrevinand spinophilin will be analyzed with Western blotting. In the second year, we will explorethe effect of male gonadal hormone since our preliminary result shows that castration reducedcortical dendritic spines. We will explore membrane electrical property changes and findingout whether exogenous testosterone reverses this. We will test whether DHEA restorescastration-induced changes? In the third year, we continue and study naturally aged femalerats. Vaginal smear and blood estrogen level will be screened to confirm anestrous. The effectof exogenous genistein and DHEA will be explored. Results obtained is expected to advanceour understanding on how gonadal hormones affect central neuronal structures and functionsand in addition provide valuable information on clinical treatment of hypogonadism forinstance following aging.
URI: http://hdl.handle.net/11455/52487
其他識別: NSC99-2320-B005-005-MY3
文章連結: http://grbsearch.stpi.narl.org.tw/GRB/result.jsp?id=2124578&plan_no=NSC99-2320-B005-005-MY3&plan_year=99&projkey=PC9907-2061&target=plan&highStr=*&check=0&pnchDesc=%E6%80%A7%E8%8D%B7%E7%88%BE%E8%92%99%E8%A3%9C%E5%85%85%E7%89%A9%E8%83%BD%E5%90%A6%E6%81%A2%E5%BE%A9%E5%A4%A7%E9%BC%A0%E5%9B%A0%E6%80%A7%E8%85%BA%E5%8A%9F%E8%83%BD%E4%B8%8D%E8%B6%B3%E8%80%8C%E9%80%A0%E6%88%90%E4%B8%AD%E6%A8%9E%E7%A5%9E%E7%B6%93%E7%B4%B0%E8%83%9E%E8%AE%8A%E5%8C%96%E4%B9%8B%E6%8E%A2%E8%A8%8E
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