學術產出-國科會研究計畫
| 題名 | 甲基化甘氨酸類似物對NMDA亞型受體選擇性作用：癲癇治療指引（第2年） Modulatory Actions of N-Methyl Glycine Derivatives on Specific Subtypes of Nmda Receptor Mediated Signaling: Implications for Epilepsy Treatment |
| 作者 | 詹銘煥 |
| 貢獻者 | 神科所 |
| 關鍵詞 | N-甲基-D-天冬氨酸受體; 甲基化甘氨酸類似物; 電生理; 鈣離子影像; 癲癇 NMDA receptor; N-methyl glycine derivatives; electrophysiology; Ca2+ imaging; epilepsy |
| 日期 | 2020-01 |
| 上傳時間 | 29-五月-2025 11:56:45 (UTC+8) |
| 摘要 | 本計畫為延續上年度核定之研究計畫，目標為持續檢測甲基甘氨酸衍生物(MGDs)對N-甲基-D-天冬氨酸（NMDA）特殊亞型受體之作用，並評估其抗痙攣之潛能，得應用於癲癇之治療。近期我們以內測前額葉皮質切片的興奮性場域電生理的成果報告顯示甲基甘氨酸(肌氨酸)可做為NMDA受體甘氨酸結合位點的共致效劑，而二甲基甘氨酸和三甲基甘氨酸(甜菜鹼)則表現為部份致效劑。調節NMDA受體甘氨酸結合位點的調控物質顯示具備治療潛力而改善癲癇或精神疾病的症狀。當麩氨酸系統及NMDA受體反應強烈時易造成痙攣，而MGDs卻可以減弱當NMDA受體活性過高所引發的癲癇發作。NMDA受體主要由NR1及NR2次單元組合而成，雖然甘氨酸結合位點坐落於NR1次單元，而甘氨酸結合位點致效劑的效力和功效則決定於NR2次單元。NMDA亞型受體的不同特性和分布可導致差異性生理及病生理訊號，明瞭NMDA受體調節物質對不同亞型受體的功效和能力將有助於掌控其選擇性藥效及治療特點。因此，三種甲基甘氨酸衍生物對特定NMDA亞型受體的作用及他們抗痙攣的功效將作檢測並比較之。本計畫將持續執行三個具體目標(1)應用小鼠癲癇模式，評估甲基甘氨酸衍生物抗痙攣之活性，以及提升抗癲癇藥物之治療效用；(2)在HEK293細胞表現不同次單元組合的重組NMDA受體，探討並比較甲基甘氨酸衍生物對麩氨酸/NMDA所誘發電流和鈣離子訊息傳遞的作用；以及(3)在不同發育階段的培養皮質神經細胞及星狀膠質細胞，檢測並比較甲基甘氨酸衍生物對麩氨酸/NMDA所引起電流、鈣離子訊息及ERK傳遞的作用。我們的研究將進一步闡明甲基甘氨酸衍生物對NMDA亞型受體的作用特質，也同時釐清甲基甘氨酸衍生物瞄準特定的NMDA受體，於新藥開發上打開前瞻性新領域，符合精神病理治療的需求，如癲癇。 The goal of this proposal will perform a continuity plan to characterize the functions of N-methyl glycine derivatives (MGDs) in N-methyl-D-aspartate receptors (NMDARs) with specific subunit types and evaluate their anticonvulsant potential for seizure treatment. Our current electrophysiological results and report indicate that N-methyl glycine (sarcosine) acts as an NMDAR co-agonist at the glycine binding site, whereas the N,N-dimethylglycine (DMG) and trimethylglycine (betaine) perform as partial agonists of NMDAR, via enhancing the excitatory field potentials in the medial prefrontal cortical slices. Modulators working on glycine binding site of NMDAR have been shown great therapeutic potential to improve the symptoms of epilepsy or psychiatric diseases. Particularly, hyper-glutamatergic response and NMDAR overactivation may induce seizures. However, MGDs could attenuate NMDAR hyperactivity. NMDARs are assembled from NR1 and NR2 subunits. Although the glycine binding site is located in NR1 subunit, the potencies and efficacies of glycine binding site agonists are dependent on the NR2 subunits. The different properties and distribution of NMDAR subtypes are involved in different physiological and pathophysiological signaling. Understanding the efficacy and potency of NMDAR modulators on different receptor subtypes will help characterize their therapeutic profiles. Accordingly, the effects of three N-methyl glycine derivatives on specific NMDAR subtypes and their anticonvulsant potential will be determined and compared. The specific aims in this study are to (1) evaluate the anticonvulsant activity of MGDs and in combination with antiepiletpic drugs for seizure therapy in mouse models, (2) investigate and compare the actions of MGDs on glutamate/NMDA mediated currents and Ca2+ signaling in HEK293 cells stably expressed recombinant NMDARs with different subunit compositions, and (3) detect and compare the effects of MGDs on glutamate/NMDA mediated currents, Ca2+ signaling, and ERK pathway in cultured cortical neurons and astrocytes at different developmental stages. Our study will elucidate the profile of MGDs on NMDAR subtypes. Understanding of MDGs targeting the specific NMDAR subtypes might open up a promising new territory for the development of novel drugs to meet the needs for tretment of psychopathological disorders, like epilepsy. |
| 關聯 | 科技部, MOST106-2320-B004-002-MY2, 106.08-108.07 |
| 資料類型 | report |
| dc.contributor | 神科所 | |
| dc.creator (作者) | 詹銘煥 | |
| dc.date (日期) | 2020-01 | |
| dc.date.accessioned | 29-五月-2025 11:56:45 (UTC+8) | - |
| dc.date.available | 29-五月-2025 11:56:45 (UTC+8) | - |
| dc.date.issued (上傳時間) | 29-五月-2025 11:56:45 (UTC+8) | - |
| dc.identifier.uri (URI) | https://nccur.lib.nccu.edu.tw/handle/140.119/157156 | - |
| dc.description.abstract (摘要) | 本計畫為延續上年度核定之研究計畫，目標為持續檢測甲基甘氨酸衍生物(MGDs)對N-甲基-D-天冬氨酸（NMDA）特殊亞型受體之作用，並評估其抗痙攣之潛能，得應用於癲癇之治療。近期我們以內測前額葉皮質切片的興奮性場域電生理的成果報告顯示甲基甘氨酸(肌氨酸)可做為NMDA受體甘氨酸結合位點的共致效劑，而二甲基甘氨酸和三甲基甘氨酸(甜菜鹼)則表現為部份致效劑。調節NMDA受體甘氨酸結合位點的調控物質顯示具備治療潛力而改善癲癇或精神疾病的症狀。當麩氨酸系統及NMDA受體反應強烈時易造成痙攣，而MGDs卻可以減弱當NMDA受體活性過高所引發的癲癇發作。NMDA受體主要由NR1及NR2次單元組合而成，雖然甘氨酸結合位點坐落於NR1次單元，而甘氨酸結合位點致效劑的效力和功效則決定於NR2次單元。NMDA亞型受體的不同特性和分布可導致差異性生理及病生理訊號，明瞭NMDA受體調節物質對不同亞型受體的功效和能力將有助於掌控其選擇性藥效及治療特點。因此，三種甲基甘氨酸衍生物對特定NMDA亞型受體的作用及他們抗痙攣的功效將作檢測並比較之。本計畫將持續執行三個具體目標(1)應用小鼠癲癇模式，評估甲基甘氨酸衍生物抗痙攣之活性，以及提升抗癲癇藥物之治療效用；(2)在HEK293細胞表現不同次單元組合的重組NMDA受體，探討並比較甲基甘氨酸衍生物對麩氨酸/NMDA所誘發電流和鈣離子訊息傳遞的作用；以及(3)在不同發育階段的培養皮質神經細胞及星狀膠質細胞，檢測並比較甲基甘氨酸衍生物對麩氨酸/NMDA所引起電流、鈣離子訊息及ERK傳遞的作用。我們的研究將進一步闡明甲基甘氨酸衍生物對NMDA亞型受體的作用特質，也同時釐清甲基甘氨酸衍生物瞄準特定的NMDA受體，於新藥開發上打開前瞻性新領域，符合精神病理治療的需求，如癲癇。 | |
| dc.description.abstract (摘要) | The goal of this proposal will perform a continuity plan to characterize the functions of N-methyl glycine derivatives (MGDs) in N-methyl-D-aspartate receptors (NMDARs) with specific subunit types and evaluate their anticonvulsant potential for seizure treatment. Our current electrophysiological results and report indicate that N-methyl glycine (sarcosine) acts as an NMDAR co-agonist at the glycine binding site, whereas the N,N-dimethylglycine (DMG) and trimethylglycine (betaine) perform as partial agonists of NMDAR, via enhancing the excitatory field potentials in the medial prefrontal cortical slices. Modulators working on glycine binding site of NMDAR have been shown great therapeutic potential to improve the symptoms of epilepsy or psychiatric diseases. Particularly, hyper-glutamatergic response and NMDAR overactivation may induce seizures. However, MGDs could attenuate NMDAR hyperactivity. NMDARs are assembled from NR1 and NR2 subunits. Although the glycine binding site is located in NR1 subunit, the potencies and efficacies of glycine binding site agonists are dependent on the NR2 subunits. The different properties and distribution of NMDAR subtypes are involved in different physiological and pathophysiological signaling. Understanding the efficacy and potency of NMDAR modulators on different receptor subtypes will help characterize their therapeutic profiles. Accordingly, the effects of three N-methyl glycine derivatives on specific NMDAR subtypes and their anticonvulsant potential will be determined and compared. The specific aims in this study are to (1) evaluate the anticonvulsant activity of MGDs and in combination with antiepiletpic drugs for seizure therapy in mouse models, (2) investigate and compare the actions of MGDs on glutamate/NMDA mediated currents and Ca2+ signaling in HEK293 cells stably expressed recombinant NMDARs with different subunit compositions, and (3) detect and compare the effects of MGDs on glutamate/NMDA mediated currents, Ca2+ signaling, and ERK pathway in cultured cortical neurons and astrocytes at different developmental stages. Our study will elucidate the profile of MGDs on NMDAR subtypes. Understanding of MDGs targeting the specific NMDAR subtypes might open up a promising new territory for the development of novel drugs to meet the needs for tretment of psychopathological disorders, like epilepsy. | |
| dc.format.extent | 116 bytes | - |
| dc.format.mimetype | text/html | - |
| dc.relation (關聯) | 科技部, MOST106-2320-B004-002-MY2, 106.08-108.07 | |
| dc.subject (關鍵詞) | N-甲基-D-天冬氨酸受體; 甲基化甘氨酸類似物; 電生理; 鈣離子影像; 癲癇 | |
| dc.subject (關鍵詞) | NMDA receptor; N-methyl glycine derivatives; electrophysiology; Ca2+ imaging; epilepsy | |
| dc.title (題名) | 甲基化甘氨酸類似物對NMDA亞型受體選擇性作用：癲癇治療指引（第2年） | |
| dc.title (題名) | Modulatory Actions of N-Methyl Glycine Derivatives on Specific Subtypes of Nmda Receptor Mediated Signaling: Implications for Epilepsy Treatment | |
| dc.type (資料類型) | report |