神經保護藥物對粒線體功能異常時鼠腦病變的影響

Abstract

3-Nitropropionic acid (3-NP)為粒線體 呼吸鏈複合體II 的抑制劑，它可在鼠導致 選擇性紋狀體病變，如同人類的Huntington 病。過去的許多研究包括我們的研究顯 示， 抑制興奮性氨基酸的釋放和施予 NMDA 受體的拮抗物，會減輕粒線體毒物 引起的腦病變。最近的研究也顯示， Dichloroacetate (DCA)對心臟衰竭及腦缺 血的鼠有保護作用。DCA 也被用於治療粒 線體腦病變。為了更進一步了解DCA 是否 也可用於減輕3-NP 所致的腦病變，及這些 藥物對腦代謝物的影響，在本計畫中，我 們利用磁共振影像(MRI)(T2 圖譜)和生物 活體磁共振質譜(in vivo 1H MRS)的變化來 評估DCA 對粒線體功能異常所引發腦病 變的治療效果。我們以3-NP 為實驗藥物， 以迷你注射器包埋於二個月大的Sprague- Dawley 株鼠腹部皮下， 並以MK- 801(2mg/kg)和DCA (100mg/kg)為治療藥 物，比較治療的效果。我們先觀察慢性3- NP 注射對鼠行為和腦病變的影響。然後觀 察DCA 對亞急性3-NP 腦病變的影響。結 果顯示慢性3-NP 注射可使鼠產生肢體障 礙類似Huntington 病，如同亞急性注射。 同時鼠腦紋狀體也會產生病變。生物活體 磁共振質譜也顯示NAA 下降，表示神經元 的死亡。於亞急性的動物模式中，DCA 的 治療並不減輕3-NP 對鼠腦紋狀體的傷 害。DCA 的臨床運用需更進一步的深入探 討其可行性。

Systemic injection of 3-nitropropionic acid (3-NP), an irreversible inhibitor of complex II in mitochondrial respiratory chain, induces selective striatal lesions in rats and non-human primates mimicking those in Huntington’s disease. In recent studies, dichloroacetate (DCA) was shown to have protective effects in rat models of cerebral ischemia and myocardial dysfunction. However, its therapeutic effect on brain lesions induced by mitochondrial dysfunction is rarely investigated. In the past year, we established an in vivo animal model to evaluate the rat brain lesions in mitochondrial dysfuction. In the present study, we compared the therapeutic effect of DCA and MK-801 by in vivo animal model. Two-month-old Sprague-Dawley rats were treated with 3-NP by continuous drug release from mini-pump, implanted subcutaneously. MK-801 (2mg/kg) and DCA (100mg/kg) were given in the same way. The rats were then evaluated by MRI (T2 maps) and in vivo 1H-MRS at indicated time points. We first evaluated the effect of chronic 3-NP injection on rats, and then evaluated the effect of DCA on the striatal lesions induced by 5-day 3-NP injection. The results showed that chronic 3-NP injection produced behavioral change and selective striatal lesions on rats. MRS also showed the decline of NAA/Cr ratio, indicating the neuronal loss or dysfunction. The simultaneous application of DCA showed no attenuation of the striatal lesions. The present results suggest that the application of DCA in brain lesions induced by mitochondrial inhibitors need further investigation.