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研究生:李君曜
研究生(外文):Chun-Yao Lee
論文名稱:抗癲癇藥物作用機轉以及顳葉型癲癇動物模式之病理學研究
論文名稱(外文):Studies on the mechanisms of antiepileptic drugs and thepathology of an animal model of temporal lobe epilepsy
指導教授:劉宏輝劉宏輝引用關係
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:114
中文關鍵詞:顳葉型癲癇症海馬迴mossy fiber sproutingglutamateGABA抗癲癇藥物
外文關鍵詞:temporal lobe epilepsyhippocampusmossy fiber sproutingglutamateGABAantiepileptic drugs
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在癲癇症中,最常見亦為最難以治療者為顳葉型癲癇症,其病理特徵主要為海馬迴的病變,其中最顯著的病理變化為型態學上出現mossy fiber sprouting(MFS),此現象亦會造成電生理學上所觀察到的,興奮性與抑制性突觸訊息的不平衡,導致神經回路過度興奮,引發癲癇症的反覆發作。其中海馬迴中的齒回,扮演控制海馬迴興奮性的樞紐:由皮質進入海馬迴的興奮性訊號,會經過齒回進入海馬迴內並將訊號往下游傳遞。在腦部放電頻率增加時,齒回可濾除高頻的電訊號,避免過度興奮對海馬迴造成傷害。然而,在大部分癲癇發作之際,過度的興奮性刺激仍會超出齒回所能保護的限度,對其下游神經元造成傷害。因此,若能強化齒回的保護作用,如使用抗癲癇藥物降低齒回突觸間的興奮性,或阻止癲癇症腦部之不正常的型態病變,將有助於癲癇症的治療。在本篇論文中,我們結合電生理學,組織學,與神經影像學的技術,觀察抗癲癇藥物在齒回突觸間之作用機制,以及利用癲癇的動物模式,尋找適當能夠抑制病態之型態學改變(MFS)之藥物,並利用神經影像學建立長期追蹤研究模式。期待此研究結果能夠對於顳葉癲癇症,提供更多藥理學以及病理生理學的基礎認識。現階段對於抗癲癇藥物作用機轉的研究,大多集中在海馬迴CA1 與皮質上,且主要著眼在於藥物對於離子通道的作用。然而,抗癲癇藥物在齒回突觸間之作用,目前則缺乏一系統性研究。我們利用電生理學的方式,研究抗癲癇藥物在齒回突觸間之作用機制。實驗結果發現,抗癲癇藥物lamotrigine 在齒回可以同時抑制AMPA 受體與glutamate 釋放,而levetiracetam 則可藉由抑制突觸前P/Q 型鈣離子通道而減少glutamate 釋放。以上之結果除了可解釋此二藥物目前尚未清楚之抗癲癇作用機轉,其在齒回區的作用,更可以提供在顳葉癲癇症產生的病變中,藥物治療的理論依據。在顳葉癲癇症的情況下,海馬迴中的GABA 系統會出現異常。雖然突觸間的GABA 反應與癲癇症的關係已有眾多的研究,然突觸外GABA 受體所調控之持續性抑制現象在癲癇症中所扮演的角色,以及其與抗癲癇藥物之間的關係,尚有待進一步釐清。在本論文中我們觀察到 GABA 所調控之持續性抑制現象在顳葉癲癇症動物模式中,有增加的情況,且可被TTX 逆轉,表現一動作電位依賴性。此結果顯示持續性抑制現象可能反映癲癇狀態中之神經活性,並可能作為抗癲癇藥物之作用標的。顳葉癲癇症中最典型的型態病變為MFS,此現象可造成興奮性與抑制性突觸間的不平衡,導致海馬迴過度興奮,並與癲癇症的反覆發作具有高度相關性。雖然我們的研究已發現抗癲癇藥物在此區的電生理作用,然而,目前在臨床與基礎研究上,並未有理想的藥物可以控制此慢性型態病變的發生。在此,我們藉由在實驗動物上引發癲癇重積狀態,建立長期慢性的顳葉癲癇症動物模式,針對此病理特徵進行藥理學以及神經影像學之研究。我們找出lovastatin 可以減少MFS 的嚴重度,此結果有助於解開MFS 之引發機制。此外,為了深入研究MFS 的機制,
並建立長期非侵入式的觀察技術,我們將擴散譜磁振造影技術應用在MFS 的觀察上,得到擴散譜磁振造影的指標與MFS 之間的相關性,此結果可提供往後長期觀察以及藥物作用評估之研究使用。總結本篇論文的實驗結果,藉由以顳葉癲癇症為研究背景,我們得到抗癲癇藥物在齒回之作用,此作用可以解釋在顳葉癲癇症中,抗癲癇藥物可藉由抑制齒回之興奮性,拮抗MFS 所引發的不正常電生理活動。此外,針對MFS,我們可利用神經影像學之長期觀察,以及藉由研究lovastatin 的作用機制,為往後解開MFS的發生機制的研究,提供有利的根基。
Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome with medical refractory characteristics. The pathophysiological changes in hippocampus, such as mossy fiber sprouting (MFS) and the imbalance between excitatory and inhibitory synaptic transmission, may cause hyperexcitabilities in the neuronal circuits and recruit spontaneous recurrent seizures (SRS). Dentate gyrus (DG), the gate of hippocampus, plays a critical role in regulating the excitability of hippocampus. DG filters high-frequency activities spreading from entorhinal cortex into hippocampus and protects neuronal damages from hyperexcitabilities. However, during seizure propagation, most seizure activities are able to overcome the dentate gate to damage the downstream neurons. To strengthen the protective effect in DG, such as to reduce the excitabilities or to prevent the foramtion of abnormal morphalogical changes, will be helpful in treating epilepsy. In the present study, we investigated the action of antiepileptic drugs on the synaptic transmission in DG by electrophysiological methods and utilized the animal model of TLE to find optimal pharmacological agents to inhibit MFS. Moreover, we established a long-term observing system for studying MFS and TLE by novel neuroimage technique. Most studies on antiepileptic drugs emphasize on their ionic channel effects in the hippocampal CA1 region and cortex, while few on synaptic actions in the DG. By whole-cell patch-clamp recording, we found lamotrigine inhibited postsynaptic AMPA receptor and glutamate release and levetiracetam inhibited glutamate transmission through presynaptic P/Q-type Ca2+ channel in the DG. These results help us to explain the antiepileptic mechanisms of these two drugs in the DG. Abnormal GABAergic transmission is also found in TLE, however, the role of extrasynaptic GABAA receptor in epilepsy is not well established. In the animal model of TLE, we found an increase of extrasynaptic GABAA receptor-mediated tonic inhibition in the granule cells of DG. This effect could be reversed by TTX, indicatingan action potential dependent mechanism which reflects the neuronal activities after the induction of epilepsy. This finding revealed a new target to develop antiepileptic drugs. The typical characteristic of TLE is MFS, which results in an imbalance between excitatory and inhibitory synaptic transmission, hyperexcitabilities in the neuronal circuits and is highly related with SRS. Although antiepileptic drugs are able to modulate electrophysiological properties, there is no ideal drug to prevent the chronic consequences. Here we established a chronic TLE animal model by inducing status epilepticus in rats and made pharmacological and neuroimage studies. We found lovastatin reduced the severity of MFS, suggesting the pharmacological mechanisms of lovastatin are related to MFS initiation. In addition, we applied the diffusion spectrum image (DSI) onto MFS observation and acquired a correlation between DSI indices and MFS, which helps us to build a long-term investigation system and evaluate the effect of pharmacological agents on MFS. In conclusion, on the background of TLE, we explained how antiepileptic drugs act on DG and exert their antiepileptic effects to antagonize the seizure activities caused by MFS, which could be inhibited by lovastatin and traced by DSI in our findings. These results help us to understand the underlying mechanisms of MFS and develop a better way to treat TLE in the future.
口試委員審定書....................................................... ii
誌謝.................................................................iii
目錄................................................................. v
圖目錄.............................................................. vii
縮寫表 (Abbreviations)................................................ ix
論文架構圖 (Frameworks) .............................................xi
中文摘要 (Abstract in Chinese)......................................... xii
英文摘要 (Abstract in English)......................................... xv
第一章 緒論 (Introduction) ............................................01
第一節 癲癇症之病理生理學....................................... 02
第二節 抗癲癇藥物在突觸間對興奮性神經傳導系統的作用機轉......... 04
第三節 GABA 調控之持續性抑制作用與癲癇症之關係................. 09
第四節 TLE 動物模式與mossy fiber sprouting........................ 10
第五節 擴散譜磁振造影在癲癇症動物模式中的應用................... 13
第二章 實驗材料與方法 (Materials and methods) ........................16
第一節 實驗動物................................................. 17
第二節 實驗藥品................................................. 17
第三節 實驗溶液配方............................................. 19
第四節 活體腦切片備製........................................... 21
第五節 全細胞膜片箝制記錄....................................... 21
第六節 顳葉癲癇症動物模式之建立................................. 24
第七節 心臟灌流與組織染色切片................................... 25
vi
第八節 擴散譜磁振造影........................................... 26
第三章 研究結果 (Results)............................................29
第一節 Lamotrigine在興奮性突觸間之作用機轉研究....................30
第二節 Levetiracetam在興奮性突觸間之作用機轉研究.................. 32
第三節 持續性抑制現象與癲癇症之關係研究.......................... 35
第四節 癲癇重積狀態後對於MFS 的藥理學研究....................... 37
第五節 擴散譜磁振造影在癲癇症動物模式之應用研究.................. 38
第四章 討論 (Discussion) ............................................40
第一節 LTG在DG 抑制突觸後AMPA 受體與glutamate 釋放............41
第二節 LEV在DG 透過突觸前P/Q 型Ca2+通道抑制glutamate 傳導...... 45
第三節 持續性抑制現象隨著發育年齡及癲癇症的引發而增加............ 50
第四節 Lovastatin 抑制MFS 之機轉討論..............................52
第五節 MFS 與DSI 指標之關聯性討論............................... 54
第五章 結論與未來展望 (Conclusion and future perspectives) ............. 58
第六章 圖表 (Figures)............................................... 60
參考文獻 (References).................................................95
著作 (Publication List) ...............................................112
vii
圖目錄
頁數(page)
附圖一 海馬回的回路示圖......................................... 04
附圖二 Glutamate 突觸示意圖......................................06
附圖三 新一代抗癲癇藥物的化學結構............................... 07
附圖四 The effect of novel antiepileptic drugs on eEPSCAMPA............ 08
附圖五 突觸外GABA 受體之持續性抑制現象示意圖.................. 09
附圖六 海馬迴內之神經傳導迴路與MFS 示意圖.......................11
附圖七 以Neo-Timm’s stain 在鼠腦組織切片上觀察到之MFS...........11
附圖八 刺激電極設置位置......................................... 21
附圖九 胞外給藥示意圖........................................... 23
附圖十 GABA 持續性抑制電流測量法............................... 24
附圖十一 癲癇重積狀態中之大白鼠................................... 24
附圖十二 Timm’s score之定義表......................................26
附圖十三 DSI 在三維q 空間中的515 個取樣點..........................27
附圖十四 鼠模型之實驗切面位置..................................... 28
Figure 1 LTG 減少eEPSCAMPA 與 eEPSCNMDA 的電流大小...............61
Figure 2 LTG 不影響 eEPSCAMPA 的PPR.............................. 62
Figure 3 LTG 抑制細胞外給予AMPA 所引發之內流電流................ 63
Figure 4 LTG 對mEPSCAMPA 的作用.................................. 64
Figure 5 LTG 抑制aEPSC........................................... 65
Figure 6 LEV 在DG 抑制eEPSCAMPA 與eEPSCNMDA 之電流大小...........66
Figure 7 LEV 改變eEPSCAMPA 的PPR................................67
Figure 8 LEV 對mEPSCAMPA 的作用.................................. 68
viii
Figure 9 LEV 抑制aEPSC 的電流大小................................. 69
Figure 10 LEV 在VDCC blockers 存在下之作用..........................70
Figure 11 在LEV 存在下,ω-AGX 對eEPSCAMPA 的作用................. 71
Figure 12 LEV 在protein kinase 抑制劑存在下之作用.....................72
Figure 13 CTC 突觸前之作用......................................... 73
Figure 14 LEV在DG突觸前抑制glutamate 釋放之作用示意圖.............74
Figure 15 TGB 與DZP 增加tonic current............................... 75
Figure 16 Tonic current 隨著發育年齡而增加............................ 76
Figure 17 Tonic current 在急性與慢性期癲癇症引發後增加................ 77
Figure 18 TTX 可以逆轉在急性期癲癇症引發後產生之tonic current 增加....78
Figure 19 在不同藥物存在下,Timm’s stain 在DG 之變化圖...............79
Figure 20 在不同藥物存在下,Timm’s score在DG與CA3之變化............80
Figure 21 Lovastatin 不影響eEPSCNMDA 之電流大小......................81
Figure 22 在不同藥物存在下,各組間之Nissl stain 圖..................... 82
Figure 23 在不同藥物存在下,DG 顆粒細胞層之厚度......................83
Figure 24 DSI 圖形重建過程圖.........................................84
Figure 25 三種不同形狀之二度空間擴散ODF 與其對應之DA 值示意圖......85
Figure 26 大白鼠腦部之擴散譜參數圖.................................. 86
Figure 27 大白鼠海馬回之磁振影像切面................................ 87
Figure 28 在DG(左側)與CA3(右側)之Timm’s scoer (0-5 分)範例圖..........88
Figure 29 在DG與CA3 之ROIs 示意圖.................................90
Figure 30 大白鼠腦部之彩色圖譜...................................... 91
Figure 31 比較控制組與SE 組之Timm''s score,MSL (a.u.)與DA............92
Figure 32 MSL 與DA 在DG 與CA3 對Timm''s score 之關聯圖.............93
Figure 33 DTI trADC 與FA 在DG 與CA3 對Timm''s score 的關聯圖........94
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