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15万人患有这种疾病。有 目前还没有已知的预防性、神经保护性或对症治疗这种毁灭性疾病的方法。 我们最近利用转基因小鼠模型发现了一种新的小脑性共济失调起始机制 通过小脑深部神经元（DCN）的过度兴奋，小脑的唯一输出途径。 小电导钙激活的K+（SK）通道是DCN放电频率的关键调节器， 在Tg小鼠的DCN神经元中沉默，具有天然存在的显性抑制性SK同种型（SK 3 -1B）， 抑制整个SK信道族。Tg小鼠在出生后第12天出现严重的小脑共济失调 其特征在于运动不协调、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， 这强烈表明，增加DCN兴奋性可能是一个重要的步骤，在这种疾病的原因。 药物降低DCN兴奋性可能为小脑性瘫痪提供一种新的治疗方法。 共济失调由于SK通道在调节DCN神经元的放电频率和阻断DCN神经元的放电频率中起关键作用， 引起增强的放电，SK通道的开放器应该减缓DCN放电并改善 小脑性共济失调的症状阿曲唑，FDA批准的用于治疗肌萎缩侧索硬化症的药物， 硬化症，已被报道是一种有效的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（SCA 2），我们发现利鲁唑在以下方面产生了显著的改善： 治疗仅4天后的运动表现。我们计划扩展这些令人兴奋的初步发现， 追求三个具体目标： 目的1：评价利鲁唑在两种共济失调动物模型中的作用; 目的2：设计一种更有效和选择性的SK开放剂，与利鲁唑不同，它不会缓慢阻断- 失活钠通道; 目的3：在两种共济失调动物模型中评价我们的新型SK开放器。 这些重要的概念验证研究将有助于确定SK通道开放器是否 构成了一种新的治疗方法，以改善显性小脑共济失调的运动表现。

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.