SK Channel Openers as Therapeutics for Cerebellar Ataxia

小脑性共济失调是一种致命的神经系统疾病，在美国约有 15 万人受其困扰。有 目前还没有针对这种破坏性疾病的已知预防、神经保护或对症治疗方法。 使用转基因小鼠模型，我们最近发现了一种引发小脑共济失调的新机制 通过深部小脑神经元（DCN）的过度兴奋，DCN是小脑的唯一输出通路。 小电导 Ca 激活 K (SK) 通道是 DCN 中放电频率的关键调节因子 Tg 小鼠的 DCN 神经元中具有天然存在的显性抑制 SK 亚型 (SK3-1B)，该亚型被沉默 抑制整个 SK 通道系列。 Tg 小鼠在出生第 12 天时出现严重的小脑共济失调 其特征是在缺乏运动能力的情况下出现运动不协调、意向性震颤和步态异常 神经变性。该模型与其他小脑共济失调动物模型的发现一起， 强烈表明 DCN 兴奋性增加可能是导致这种疾病的重要一步。 降低 DCN 兴奋性的药物可能为小脑神经损伤提供一种新的治疗方法 共济失调。由于 SK 通道对于调节 DCN 神经元的放电频率及其封锁至关重要 导致增强发射，SK 通道的开启器应该减慢 DCN 发射并改善 小脑性共济失调的症状。利鲁唑（Riluzole），FDA 批准用于治疗肌萎缩侧索硬化症的药物 据报道，它是一种有效的 SK 通道开放剂。在 Tg 小鼠模型的初步研究中 对于人类脊髓小脑共济失调 2 型 (SCA2)，我们发现利鲁唑可显着改善 仅治疗 4 天后的运动表现。我们计划通过以下方式扩展这些令人兴奋的初步发现 追求三个具体目标： 目标 1：在两种共济失调动物模型中评价利鲁唑； 目标 2：设计一种更有效、更具选择性的 SK 开启剂，与利鲁唑不同，它不会缓慢阻断 - 使钠通道失活； 目标 3：在两种共济失调动物模型中评估我们的新 SK 开启剂。 综上所述，这些重要的概念验证研究将有助于确定 SK 渠道开放者是否 构成了一种改善显性小脑共济失调运动表现的新治疗方法。

Cerebellar ataxia is a lethal neurological disease, which afflicts about 150,000 people in the US. There are currently no known preventive, neuroprotective or symptomatic treatments for this devastating disease. Using a transgenic mouse model we recently identified a novel mechanism of initiation of cerebellar ataxia through hyperexcitability of the deep cerebellar neurons (DCN), the sole output pathway of the cerebellum. Small conductance Ca -activated K+ (SK) channels, key regulators of firing frequency in the DCN, were silenced in DCN neurons of Tg mice with a naturally occurring dominant-inhibitory SK isoform (SK3-1B) that suppresses the entire SK channel family. Tg mice developed severe cerebellar ataxia by the 12th day of life characterized by motor incoordination, intention tremor and gait abnormalities in the absence of neurodegeneration. This model, together with findings from other animal models for cerebellar ataxia, strongly suggests that increased DCN excitability may be an important step in the causation of this disorder. Pharmacological reduction of DCN excitability may provide a novel therapeutic approach for cerebellar ataxia. Since SK channels are critical in regulating the firing frequency of DCN neurons and their blockade causes enhanced firing, an opener of SK channels should slow down DCN firing and ameliorate the symptoms of cerebellar ataxia. Riluzole, a FDA approved drug for the therapy of amyotrophic lateral sclerosis, has been reported to be a potent SK channel opener. In a preliminary study in a Tg mouse model for human spinocerebellar ataxia type 2 (SCA2), we found that riluzole produced a dramatic improvement in motor performance after only 4 days of treatment. We plan to extend these exciting preliminary findings by pursuing three specific aims: Aim 1: Evaluation of riluzole in two animal models of ataxia; Aim 2: Design of a more potent and selective SK opener that unlike riluzole does not block slowly- inactivating sodium channels; Aim 3: Evaluation of our new SK opener in two animal models of ataxia. Taken together these important proof-of-concept studies will help to determine whether SK channel openers constitute a new therapeutic approach to improve motor performance in dominant cerebellar ataxias.