The effect of dextromethorphan on the

Dextromethorphan(DM) 為臨床上使用 40 年以上的非麻醉性止咳劑。在先前的 研究發現 DM 是一種 NMDA(N-methyl-D-aspartate) 接受體的離子通道阻斷劑。

NMDA 接受體是 voltage-gated 離子通道，當它被活化時，引起細胞膜去極化

，引發鈣離子內流，導致細胞興奮性增加，而細胞內鈣離子濃度增加會進一步 活化細胞的重要酵素，而引發一連串的生理或病理反應。因此 DM 具有拮抗 N MDA 接受體所引發的腦神經生理或病理的變化。過去的報告發現， DM 在成 鼠腦中具有抑制抽搐的作用，因此本實驗欲了解 DM 在發育時期的幼鼠腦中是 否有同樣的作用，故以幼鼠為實驗動物，利用 pentylenetetrazol (PTZ) 及 -hydr oxybutyric acid (GHB) 誘發癲癇抽慉發作的產生，再投予 DM 來了解是否有抑 制或減緩的效果。此外，為進一步探討持續或過劇烈的抽搐是否會影響腦部促 細胞計劃性死亡基因表現的影響，我們利用反轉錄聚合脢鏈鎖反應 (Reverse tra nscription-polymerase chain reaction ； RT-PCR) 的方法偵測 PTZ 對大腦皮質中 c-fos 、 c-jun 、 bcl-2 及 bax mRNA 的表現之影響，並且了解 DM 是否也具有 減少因抽搐引起的腦神經細胞死亡的功用。而由實驗結果發現： (1) DM 可抑 制第 14 、 30 及 60 天大的老鼠，經 PTZ 所誘發的 generalized clonic-tonic seizur e ，但對其餘的抽搐行為並無明顯的抑制作用。 (2) DM 可以藉由降低 bcl-2/ba x ratio 來抑制 apoptosis 的產生。因此在臨床治療的使用上，我們預期 DM 可 為一安全、易取得並且副作用小的抗抽搐藥物，可用在較大歲數幼童之 general ized clonic-tonic seizure 。

探討 Dextromethorphan 對 Pentylenetetrazol 及 gamma-hydroxybutyric acid 誘發幼鼠癲癇行為之 效應以及腦中 bax 及 bcl-2 基因之表現

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Dextromethorphan (DM) is an effectively and widely used nonnarcotic antitussive agen t for 40 years. Recent investigations have indicated that DM is an N-methyl-D-aspartate (NMDA) receptor antagonist. In particularly, DM could prevent or inhibit the NMDA re ceptor-mediated neuropathology including hypoxia-ischemia neurotoxicity and seizure activity. DM produces these effects by blocking the NMDA receptor coupled ion chann el. However, most of the studies were conducted on adult animals and adult patients. Th e anticonvulsant effect of DM on the seizure activity occuring during the developing ag e is not yet well determined. We would like to investigate whether DM can effectively a ttenuate the chemical-induces seizure and brain damage in developing rats. The chemica l materials used to induced seizure are pentylenetetrazol (PTZ) and gamma-hydroxybut yric acid (GHB), which induce absence-like seizure and generalized clonic-tonic seizure . Otherwise, the effect of DM on brain damage from PTZ and GHB-induced seizure in d eveloping rat were investigated herein. The phenomenon were studied using the Revers e transcription-polymerase chain reaction (RT-PCR) to detect c-jun, c-fos, bcl-2 and ba x mRNA expression. Our results showed that (1). In animal seizure models, DM attenua ted the generalized clonic-tonic seizure of PND (post-natal day) 14, 30 and 60 rats. (2).

In RT-PCR experiments, DM would inhibit apoptosis in lowing bcl-2/bax ratio. The res ults of our studies suggest that DM have anticonvulsant effect in treating generalized cl onic-tonic seizure of PND 30 and 60 rats. And we can use DM to cure generalized cloni c-tonic seizure in older children.

The effect of dextromethorphan on the

pentylenetetrazol and gamma-hydroxybutyric acid

induced-seizure behavior and bax and bcl-2 gene

expression in the developing rat brain.