ENT1抑制劑作為癲癇藥物開發之評估

Abstract

研究指出腺苷能調節神經過度的衝動，因此維持腦部高腺苷濃度應能有效治療癲癇。根據先前的研究結果，equilibrative nucleoside transporter 1 (ENT1)的抑制劑，能夠有效地增加細胞外液的腺苷濃度。因此本研究將利用三種癲癇動物模型來評估兩種ENT1抑制劑作為抗癲癇藥物的潛力。首先，代表強直-陣攣型癲癇的maximal electroshock seizure (MES) 動物模型中，兩種測試藥物在高劑量的情況下都能夠有效的縮短發作後的症狀持續時間，其中J7更能夠有效的抑制癲癇發作。其次再以高劑量腹腔注射pentylenetetrazole (PTZ) 所誘發之肌痙攣型癲癇此模型上，兩種藥物在較低劑量都能有效延遲癲癇發作的效果，其中J7的延遲效果十分顯著，並在分析其行為表現後，發現J7能夠有效的抑制癲癇級數，但J4無法在癲癇發作後有效的抑制其行為表現。 最後，我們以低劑量PTZ來造成腦部慢性的永久損傷之動物模型 (Kindling模型) 來評估病發後給予藥物之治療效果，有別於急性動物模型，這個模型透過觀察腦波來評估其癲癇是否有反覆發作的情形，在確認成功誘發後，於每天固定時間給予兩種測試藥物，持續一周後停止藥物治療，並繼續觀察一周評估其治療情況。根據實驗結果，在給予藥物治療期間，J7與J4都能夠有效地降低癲癇發作的時間與次數，其中J7的抑制效果又與藥物carbamazepine (CBZ) 相似。 這些結果顯示，J7及J4在兩種急性與一種慢性癲癇模型下都展現出抗癲癇的效果，而其中又以J7更具發展潛力。

As adenosine can regulate the excitability of neuron cells, it can be effective in the treatment of epilepsy by maintaining high levels of adenosine in the brain. Previous study has shown that, the inhibition of equilibrative nucleoside transporter 1 (ENT1) can increase brain extracellular levels of adenosine. Thus, the present study aimed to assess the effectiveness of ENT1 inhibitors on the treatment of epilepsy using three epilepsy animal models. First, the maximal electroshock seizure (MES) animal model was used to evaluate the effectiveness of ENT1 inhibitors on tonic-clonic epilepsy. The results showed that high dose of J7 and J4 can effectively decrease the duration of seizure after the seizure occurred. J7 was also effective in inhibiting the occurrence of seizures. Second, acute epilepsy model established by high-dose intraperitoneal injection of pentylenetetrazole (PTZ) was used to evaluate the effectiveness of ENT1 inhibitors on myoclonic epilepsy. In this model, both test drugs can effectively delay the seizures onset, in which J7, but not J4, was able to comprehensively inhibit the Racine’s score. Finally, chronic animal model (Kindling model) induced by low-dose PTZ was use to assess the therapeutic effect of these drugs on permanent chronic brain damage. In this model, both J7 and J4 were able to reduce the time and frequency of seizures. The effect of J7 was similar to that of carbamazepine (CBZ). These findings showed that both J7 and J4 exhibit antiepileptic effects in both acute and chronic epilepsy models. Especially, J7 can be more promosing for further anti- epileptic development.