顳葉癲癇是成人常見的頑固性癲癇病因之一，有約三分之一患者仍無法達到理想癲癇控制，且大多藥物僅是症狀控制，無法預防癲癇生成。我們將於本實驗中探討傳統中藥天麻其活性藥理成分天麻素 (gastrodin)及天麻苷元 (gastrodigenin) 於lithium-pilocarpine 誘發癲癇重積動物模式中是否可減輕癲癇嚴重度及抑制神經興奮毒性並探討相關背後機轉。
我們利用行為觀察及動物腦波記錄來探討經天麻素及天麻苷元處理後，在lithium-pilocarpine 誘發癲癇重積動物模式中癲癇發作之程度。病理組織切片探討急性與亞急性海馬迴神經元損傷程度。膜片鉗實驗研究在天麻素及天麻苷元處理下不同離子通道的電生理特性改變。以西方墨點法探討在經天麻素及天麻苷元處理過的大鼠海馬迴其γ-氨基丁酸傳遞及離子通道的蛋白質表現變化。
在本實驗中，我們發現天麻素及高劑量的天麻苷元可降低癲癇嚴重程度及抑制癲癇樣放電波之生成。天麻素也展現了神經保護之功能。於膜片鉗實驗中，天麻素及天麻苷元可抑制L型鈣離子電流及M型鉀離子電流，但對於鈉離子通道並無調節作用。西方墨點法研究發現天麻素及天麻苷元可抑制L型鈣離子通道及M型鉀離子通道的蛋白質表現，也可減少γ-氨基丁酸A型受體在癲癇發作後的降解。
天麻素及高劑量的天麻苷元的純化合物在癲癇重積動物模式中可減少癲癇發作造成的興奮性毒性，可提供神經元保護之效果。其對於鈣、鉀離子通道電流之調控及增強γ-氨基丁酸傳遞在抗癲癇機轉上扮演重要角色。未來可做為研發新的抗癲癇藥之選項。

Temporal lobe epilepsy remains one of drug-resistant focal epilepsy among adult epilepsy syndromes. Only two-third patients become seizure-free with current medical treatment. Many research efforts aim to develop new intervention strategies or drug repurposing from the traditional herb medicine to treat epilepsy and ameliorate the seizure related neuronal excitoxicity. Herein, we conducted a study to determine whether pure synthetic gastrodin and its active aglycone metabolite gastrodigenin can reduce lithium-pilocarpine induced seizure severity and neuronal excitotoxicity. The underlying mechanism was investigated.
We performed the behavioral analysis and electroencephalography to determine the effect of gastrodin and gastrodigenin on the seizure severity induced by lithium-pilocarpine injection. Histopathologic examination elucidated the degree of rat hippocampal neuronal damage as markers of acute and subacute neuronal excitotoxicity. In in vitro studies, the patch clamp examination was used to clarify the alteration of electrophysiological properties of different ion channels with treatment of gastrodin and gastrodigenin. The Western blot experiment was carried out to demonstrate the protein expression of GABAergic neurotransmitters and ion channels after addition of gastrodin and gastrodigenin in the rat hippocampus.
We found that gastrodin and high-dose gastrodigenin reduced the acute seizure severity in lithium-pilocarpine-induced seizure model. In EEG recording, gastrodin and high-dose gastrodigenin demonstrated inhibitory effect of epileptiform discharge. Gastrodin also exhibited neuroprotection effect against seizure related hippocampal neuronal damage. The patch clamp studies revealed that gastrodin and gastrodigenin suppressed L-type Ca2+ current. Surprisingly, gastrodin and gastrodigenin also demonstrated the effect of inhibitory action on M-type K+ current. However, the Na+ current did not alter as gastrodin or gastrodigenin was added. The Western blot experiment showed that gastrodin and gastrodigenin inhibited the protein expression of L-type Ca2+ channel subunit (Cav1.2) and M-type K+ channels (Kv7.2). Besides, gastrodin and gastrodigenin attenuated the degradation of GABAA receptor after pilocarpine-induced seizure.
In the in vivo and in vitro studies, we could conclude that gastrodin and gastrodigenin reduced the seizure severity and neuronal excitotoxicity induced by lithium-pilocarpine model and provided the effect of neuroprotection. The ionic effects and GABAergic modulation of gastrodin and gastrodigenin play an important role in their antiepileptic mechanism. The results offer a new insight of searching new antiepileptic drugs from traditional Chinese medicine.

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