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
