臺灣博碩士論文加值系統

熱中風病患的臨床表現是高體溫，神經功能異常及多種器官病變。近年來，將實驗動物置於熱環境 (42℃) 會誘發熱中風，而且熱中風會造成顱內高壓，系統低血壓產生中樞神經系統的症狀，包括大腦 dopamine, serotonin 及 glutamate 過度製造以及大腦缺血損害。
由於對熱中風的治療並無有效藥物。因此，本次的實驗嘗試利用大鼠熱中風實驗模式來找出高容積性稀釋法，dl-tetrahydropalmatine, 及 nimodipine 的治療潛力。
高容積性稀釋法是利用靜脈注射 10% 人類白蛋白方式。大腦紋狀體的相對及絕對血流量是各利用雷射都卜勒儀及自動放射顯影可擴散追蹤劑方法測量得到。
利用活體微透析技術來測量紋狀體的 dopamine 釋出量。和正常溫度對照組大鼠比較，實驗大鼠注射生理食鹽水或肝素抗凝全血增加容積，在熱中風誘發後都表現出 dopamine 釋出增加；同時 striatum, hypothalamus 或皮質的神經細胞損傷指數增加，而平均動脈壓降低，striatum, hypothalamus 或皮質大腦血流減少。
然而，熱中風所誘發的低血壓，大腦缺血，紋狀體 dopamine 過度製造及神經細胞損傷指數增加會因為在熱中風誘發前或發作後靜脈注射 10% 白蛋白而減輕，這樣的治療同時會產生高容積及血液稀釋的效應。
另外，在熱中風發作後持續滴注血管增壓劑 phenylephrine (2 mg Kg-1 min-1)，並沒有辦法維持適當平均動脈壓，而無法保護大鼠熱中風傷害，所以，這種結果顯示注射 10% 白蛋白所獲得的效果是因為血液稀釋及／或維持平均動脈血壓。延胡索是一種中醫常用來治療腹痛安全有效的中草藥，dl-tetrahydropalmatine是由延胡索分離出來的主要有效成分，它有鎮痛、鎮靜、安神及抗高血壓療效。在本實驗的結果，熱中風所誘發的高體溫，低血壓，大腦缺血，大腦單胺過度製造及大腦神經細胞損傷皆可因前處理 dl-tetrahydropalmatine 而減輕。由此可知 dl-tetrahydropalmatine 提供熱中風大鼠神經保護效果。
Nimodipine 是腦妥的有效成分，它有抗大腦血管痙攣及抗缺血的作用，許多血管活性物質或血液分解物質在離體實驗會造成血管收縮可以藉 nimodipine 預防或減輕。
在本實驗中，熱中風的發作時間（從開始加熱到熱中風發作的間隔）及存活時間（熱中風發作到心跳停止間隔）都已確定。我們發現高容積稀釋法和 dl-tetrahydropalmatine 雖不能改變熱中風發作時間，但會延長大鼠在熱中風發作後的存活時間。
相反的，注射 nimodipine 治療的大鼠，不管熱中風發作時間或熱中風發作後的存活時間皆會縮短，表示 nimodipine會減弱大鼠對熱的抵抗力。
綜合本實驗的結果，顯示高容積稀釋法（靜脈注射 10% 白蛋白）或dl-tetrahydropalmatine 對大鼠的實驗熱中風模式有治療效果。

Patients with heatstroke display hyperthermia, neurological abnormalities and multiple organ disorders. Previously, we have exposed the animal to a hot environment (42℃) to induce heatstroke, showing cerebral dopamine, serotonin and glutamate overload, and ischemic injury resulting from intracranial hypertension and arterial hypotension are responsible for occurrence of central nervous system, syndromes associated with heatstroke. No pharmacological agent has been found to be beneficial in the treatment of heatstroke. Therefore, in the present study, we attempted to test the therapeutic potentials of hypervolemic hemodilution, dl-tetrahydropalmatine and nimodipine treatment in a rat heatstroke model.
Hypervolemic hemodilution was produced by intravenous administration of 10% human albumin. Relative and absolute blood flow in the corpus striatum were determined using the laser Doppler flowmetry and the autoradiography diffusible tracer technique, respectively. The dopamine release in the striatum was estimated using the in vivo microdialysis technique. After onset of heatstroke, animals with hypervolemic state alone, produced by saline or heparinized blood injection, displayed higher values of dopamine release, as well as neuronal damage score in the striatum, hypothalamus, or cortex, but lower values of mean arterial pressure and blood flow in the striatum, hypothalamus, or cortex compared to normothermic contrals. However, the heatstroke-induced arterial hypotension, cerebral ischemia, increases striatal dopamine overload, and increased neuronal damage score were attenuated by induction of both hypervolemic and hemodilution state with 10% albumin either before or after the onset of heatstroke. In addition, constant infusions of a vasopressor agent phenylephrine (2 mg kg-1 min-1) after the onset of heatstroke failed to maintain appropriate levels of mean arterial pressure and resulted in no protection against heatstroke. Thus, it appears that the observed benefit of the 10% albumin is secondary to hemodilution and/or maintenance of mean arterial pressure.
Corydalis, is recognized as a safe and often effective remedy for abdominal pain by practitioners of Chinese herbal medicine. DL-Tetrahydropalmatine, an active principle isolated from corydalis, possesses analgesic, sedative, hypnotic and antihypertensive effects. In the present results, the heatstroke-induced hyperthermia, arterial hypotension, cerebral ischemia, brain monoamine overload, and cerebral neuronal injury were attenuated by pretreatment with dl— tetrahydropalmatine. The data indicate that dl-tetrahydropalmatine provides neuroprotective effect in heatstroke.
Nimodipine, the active ingredient of Nimotop, has a predilective cerebral antivasoconstrictive and antiischemic activity. Vasoconstriction provoked in vitro by various vasoactive substances or by blood and blood degradation products can be prevented or eliminated by nimodipine. In the present study, both the latency of heatstroke onset (interval between the start of heat exposure and the onset of heatstroke) and survival time (interval between the onset of heatstroke and cardiac arrest) were defined. It was found that both hypervolemic hemodilution and dl-tetrahydropalmatine, although having no effect on the latency of heatstroke onset, prolonged the survival time in rats with heatstoke. In contrast, both the latency of heatstroke onset and the survival time were all attenuated by nimodipine treatment. It seems that nimodipine impair the resistance of rats in the heat.
In conclusion, the present results suggest that hypervolemic hemodilution (produced by intravenous infusions of 10% albumin) and/or dl-tetrahydropalmatine are beneficial in the treatment of heatstroke in a rat model.

封面
中文摘要
英文摘要
第一章　緒論
第一節　大鼠熱中風模式
第二節　高容積性稀釋法之應用
第三節　腦妥靜脈注射液之應用
第四節　腦妥靜脈注射液之應用
第五節　研究目的
第二章　實驗材料與方法
第一節　高容積性稀釋法的材料與實驗方法
一、實驗動物
二、動物手術及生理參數監測
三、熱中風誘發
四、動物分組
五、大腦血流測定
六、大腦紋狀體細胞外液多巴胺的測量
七、免疫組織化學染色法
八、腦神經細胞損傷指數判定
九、胺基酸的神經毒性探討
十、統計學分析
第二節　DL-四氫巴馬汀實驗的材料與方法
一、實驗動物
二、動物分組
三、大腦血流測定
四、大腦單胺變化的測定
五、大腦病理組織學與神經細胞損傷指數的探討
六、統計學分析
第三節　Nimodipine實驗的材料與方法
一、實驗動物
二、動物分組
三、大腦血流測定
四、大腦單胺變化的測定
五、大腦病理組織學與神經細胞損傷指數的探討
六、統計學分析
第三章　實驗結果
一、高容積性稀釋法實驗的結果
二、DL-四氫巴馬汀實驗的結果
三、Nimodipine實驗的結果
第四章　討論
第五章　結論
參考文獻
附錄

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