Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J Neurosci. 2010 May 26;30(21):7249-57. doi: 10.1523/JNEUROSCI.6341-09.2010.
Episodic ataxia type-2 (EA2) is an inherited movement disorder caused by mutations in the gene encoding the Ca(v)2.1alpha1 subunit of the P/Q-type voltage-gated calcium channel that result in an overall reduction in the P/Q-type calcium current. A consequence of these mutations is loss of precision of pacemaking in cerebellar Purkinje cells. This diminished precision reduces the information encoded by Purkinje cells and is thought to contribute to symptoms associated with this disorder. The loss of the precision of pacemaking in EA2 is the consequence of reduced activation of calcium-dependent potassium channels (K(Ca)) by the smaller calcium current and in vitro can be pharmacologically restored by K(Ca) activators. We used a well established mouse model of EA2, the tottering (tg/tg) mouse, to examine the potential therapeutic utility of one such Food and Drug Administration (FDA)-approved compound, chlorzoxazone (CHZ). Compared with wild-type Purkinje cells, we found the firing rate of tg/tg Purkinje cells in acutely prepared cerebellar slices to be very irregular. Bath application of CHZ successfully restored the precision of pacemaking in a dose-dependent manner. Oral administration of CHZ to tg/tg mice improved their baseline motor performance and reduced the severity, frequency, and duration of episodes of dyskinesia without producing any adverse effects. We propose the use of CHZ, which is currently FDA approved as a muscle relaxant, as a safe and novel treatment of EA2.
发作性共济失调 2 型（EA2）是一种遗传性运动障碍，由编码 P/Q 型电压门控钙通道的 Ca(v)2.1alpha1 亚基的基因突变引起，导致 P/Q 型钙电流总体减少。这些突变的一个后果是小脑浦肯野细胞起搏精度的丧失。这种精度的降低减少了浦肯野细胞编码的信息，被认为与该疾病相关的症状有关。EA2 起搏精度的丧失是由于较小的钙电流对钙依赖性钾通道（K(Ca)）的激活减少所致，在体外可以通过 K(Ca)激活剂药理学恢复。我们使用了一种成熟的 EA2 小鼠模型，即 tottering（tg/tg）小鼠，来研究一种已获得美国食品和药物管理局（FDA）批准的化合物，氯唑沙宗（CHZ）的潜在治疗效用。与野生型浦肯野细胞相比，我们发现急性小脑切片中 tg/tg 浦肯野细胞的放电率非常不规则。CHZ 的浴应用以剂量依赖性方式成功恢复了起搏精度。CHZ 对 tg/tg 小鼠的口服给药改善了它们的基础运动表现，并降低了运动障碍发作的严重程度、频率和持续时间，而没有产生任何不良反应。我们建议使用 CHZ，它目前被 FDA 批准为肌肉松弛剂，作为 EA2 的一种安全且新颖的治疗方法。
