臺灣博碩士論文加值系統

癲癇是第二大常見的神經性疾病，不只干擾患者的運動協調功能，也會妨礙其心理、記憶及辨識能力，導致認知功能損傷，其病理機轉包含興奮性神經傳遞物質麩胺酸 (glutamate)太多，但抑制性神經傳遞物質gamma-aminobutyric acid (GABA)太少所致。Val為GABA受體致效劑，是臨床第一線抗癲癇藥物之一，然而副作用多。CEF可以增加麩胺酸轉運子 (glutamate transporter-1, GLT-1)以減少glutamate含量，具有神經新生及神經保護的效果。本研究主要探討以下議題：(1)探討CEF及Val對癲癇大鼠之發作強度、運動協調及認知功能的效果。(2)探討CEF及Val在神經保護、神經新生及細胞凋亡的效果。(3)合併使用較低劑量之CEF及Val是否具有相乘效果(synergistic effect)。本研究使用雄性Wistar大鼠為實驗動物，並以pentylenetetrazole (PTZ, 35 mg/kg, i.p.)每間隔一天注射一次(共7次，13天)進行誘發。在第4次誘發後當天(第7天)給予CEF(10或50 mg/kg)、Val(50或100 mg/kg)或合併投予CEF及Val連續治療一周 (到第13天)。大鼠在被誘發癲癇模型前，接受滾輪試驗(rotarod test)以評估運動協調功能的基礎值，在第14天進行後測。第15-17天進行物件辨識試驗評估物件辨識功能，第18-20天進行被動迴避試驗以評估記憶，第21天進行挑戰，第22天注射BrdU以標定新生細胞，第23天犧牲取腦進行神經組織學分析。結果顯示癲癇大鼠發作嚴重且有較差的運動協調與認知功能；接受CEF(10與50 mg/kg)與Val(100 mg/kg)治療可降低發作強度，改善運動協調及認知功能。有趣的是，當合併低劑量CEF(10 mg/kg)與無效劑量Val(50 mg/kg)治療，在行為上同樣具有良好的治療效果，且停藥一周效果仍在(因為行為實驗期間無任何藥物的介入)。在組織學上發現，癲癇大鼠之海馬迴區域的神經密度較低且新長細胞數量較少，但是杏仁核區域凋亡細胞較多。然而上述神經組織學之缺陷可以透過CEF、Val、合併投予低劑量之CEF及Val治療而獲得改善。本研究指出CEF可能與Val同樣具有抑制癲癇的效果。此外，併用低劑量CEF與Val可以加大這兩種藥物改善運動協調、認知功能及神經保護的功能，顯示出相乘效果。【由於專利布局所需，摘要內之關鍵藥品名稱暫以縮寫呈現。】

Epilepsy is the second most common neurological disorder, which causes not only motor dysfunction, but also cognitive impairments in recognition, memory, and mental function. The pathophysiology of epilepsy includes excessive excitatory neurotransmitter, glutamate, and insufficient level of inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Val, a GABA agonist, is one of the first-line antiepileptic drugs but shows adverse side effects. Previous studies indicated that CEF increases the expression of glutamate transporter-1 (GLT-1), reduces glutamate level, increases neurogenesis, and shows neuroprotection in animal studies. The purposes of this study were: (1) investigating the effects of CEF and Val on seizure, motor, and cognitive function in epilepsy rat model. (2) investigating the effects of CEF and Val on neuroprotection, neurogenesis, and apoptosis. (3) investigating the effects of combination of low dose of CEF and Val on the above behavioral and neuronal functions. Male Wistar rats were used in this study and trained in rotarod to measure motor function at baseline. Then all the rats were injected with pentylenetetrazole (PTZ, 35 mg/kg/every other day, i.p., for 13 days) to induce epilepsy model. CEF (10 or 50 mg/kg), Val (50 or 100 mg/kg), or combination of CEF and Val were administered starting from the 4th PTZ injection for 7 consecutive days, till the day 13. The rats were tested in rotarod (on day 14) for measuring motor function, in object recognition test (on days 15-17) for measuring recognitive function, and in passive avoidance test (on days 18-20) for measuring memory. Noteworthy, no drugs were administered during the behavioral tests. The rats received challenge on day 21 and received BrdU (150 mg/kg) injection on day 22. All rats were sacrificed with brain being taken for histological examination on day 23. Epilepsy rats showed seizure and impairments in motor and cognitive functions. Treatments with CEF and Val dose-dependently reduced seizure and improved motor and cognitive functions. Interestingly, combination of CEF (10 mg/kg) and Val (50 mg/kg) showed also beneficial effects on behavior. Histologically, epilepsy rats showed lower neuronal density and neurogenesis in the hippocampus but higher apoptosis in the amygdala, compared with control, which were restored by the treatment with CEF, Val, and combination of CEF and Val. The study indicated that CEF may be as effective as Val in suppressing seizure. Moreover, combination of low dose of CEF and Val showed also neuroprotection and improvement in motor and cognitive functions in epilepsy, indicating synergistic effect. 【For patenting, drug names are expressed as abbreviations.】

目錄
1. 前言 10
2. 材料與方法 19
2.1. 動物 19
2.2. 前驅試驗(pilot study) 19
2.3. 一般程序 20
2.4. Pentylenetetr1azole(PTZ)誘發大鼠產生癲癇模型 21
2.5. 行為實驗 22
2.5.1. 滾輪試驗 (rotarod test) 22
2.5.2. 被動迴避試驗 (passive avoidance test; PAT) 22
2.5.3. 物件辨識試驗 (object recognition test ) 23
2.6. 組織學分析 24
2.6.1. 組織灌流 24
2.6.2. 冷凍切片 24
2.6.3. 尼氏染色法 (Nissl stain) 25
2.6.4. 酪胺酸羥化酶(Tyrosine hydroxylase；TH)染色 25
2.6.5. 神經新生 5-bromo-2'-deoxyuridine (BrdU)染色 26
2.6.6. 凋亡細胞terminal deoxynucleotidyl transferase(TdT) dUTP nick end labeling assay (TUNEL)染色 26
2.7. 影像定量分析 27
2.8. 統計方法 28
3. 結果 28
3.1. 行為實驗 28
3.1.1. CEF與Val治療癲癇模型的結果 28
3.1.2. 滾輪試驗 (rotarod test)：運動協調功能 33
3.1.3. 被動迴避試驗 (passive avoidance test; PAT)：記憶功能 34
3.1.4. 物件辨識試驗 (object recognition test)：辨識功能 35
3.2. 組織學分析 37
3.2.1. 尼氏染色 (Nissl stain) 37
3.2.2. 酪胺酸羥化酶染色(tyrosine hydroxylase stain；TH) 41
3.2.3. 神經新生BrdU染色： 海馬迴齒狀回區域之神經新生 43
3.2.4. 凋亡細胞TUNEL染色：杏仁核區域之神經細胞凋亡 44
4. 討論 46
4.1. 建立癲癇大鼠疾病模型 46
4.1.1. 癲癇大鼠模型效度檢驗 46
4.1.2. 行為的缺損 48
4.1.3. 神經系統的缺損 50
4.2. 藥物治療；頭孢曲松與丙戊酸 54
4.2.1. 頭孢曲松 55
4.2.2. 丙戊酸(valproic acid, Val) 57
5. 參考文獻 62

圖目錄
圖1-1. 癲癇患者藥物控制程度 11
圖1-2. 麩胺酸神經訊遞與造成細胞凋亡之機轉示意圖 14
圖1-3. 癲癇之生理病理與本研究藥物之可能作用機轉。 17

圖2-1. 前驅試驗 20
圖2-2. 實驗流程 21
圖2-3. 迴避試驗 23
圖2-4. 物件辨識試驗之物件擺設與實驗流程示意圖 24

圖3-1. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠發作強度之效果 30
圖3-2.以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠僵直-痙攣型發作的潛伏期之效果 32
圖3-3. ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠僵直-痙攣型發作的持續時間之效果 33
圖3-4. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠之運動協調功能之效果 34
圖3-5. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠記憶之效果 35
圖3-6. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠在物件辨識試驗中探索新物件(new object)與舊物件(old object)之時間百分比之效果 37
圖3-7. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠海馬迴CA1神經缺損的效果 38
圖3-8. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠海馬迴l-CA3神經缺損的效果 39
圖3-9. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠海馬迴m-CA3神經缺損的效果 40
圖3-10. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠海馬迴DG神經缺損的效果 41
圖3-11. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠紋狀體內多巴胺神經纖維末梢密度的效果 42
圖3-12. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠黑質體多巴胺神經元密度的效果 43
圖3-13. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠之海馬迴齒狀回區域內神經新生的效果 44
圖3-14. 以ceftriaxone (CEF)與valproate (Val)治療對癲癇大鼠之基底外側杏仁核區域內凋亡細胞的效果 45

圖4-1. ceftriaxone與cefixime的化學結構 57
圖4-2. 評估健康組與癲癇患者之杏仁核內 basolateral complex及centromedial nuclei內凋亡細胞之數量 61
 
表目錄
表1-1. 常見之抗癲癇藥物的副作用 18

表4-1. 臨床上各種類型癲癇之常用藥物及藥理機轉 59

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