PDF(Pubmed)
Abstract：
Loss-of-function mutations in the KCNA1(Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by KCNA1 mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation-induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a knock-in mouse model of EA1 and restored the neuromuscular transmission and climbing ability in Shaker (Kv1.1) mutant Drosophila melanogaster flies (Sh5). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.
摘要：
KCNA1（Kv1.1）基因的功能缺失突变导致1型发作性共济失调（EA1），一种以小脑功能障碍为特征的神经系统疾病，共济失调发作,持续的肌强直伴骨骼肌疼痛痉挛，和癫痫。目前用于EA1治疗的精准医学是不可行的,因为没有一种药物能够增强含Kv1.1通道的活性并抵消由KCNA1突变引起的功能缺陷。这里,我们发现尼氟灭酸(NFA)，目前规定的镇痛和抗炎药在临床上具有良好的安全性，增强Kv1.1通道的活性。NFA通过增强通道开放概率来增加Kv1.1电流幅度，在通道打开和门控电荷运动的电压依赖性中引起超极化偏移，减慢关闭门控电流衰减。NFA对同聚Kv1.2和异聚Kv1.1/Kv1.2通道都有类似的作用，在大多数大脑结构中形成。我们表明，通过它的增强作用，NFA减轻了Kv1.1中EA1突变诱导的功能缺陷，并恢复了小脑突触传递，浦肯野细胞可用性，和精确的射击。此外,NFA改善了EA1敲入小鼠模型的运动性能，并恢复了Shaker（Kv1.1）突变果蝇果蝇（Sh5）的神经肌肉传递和攀爬能力。凭借其多重行动，NFA具有作为EA1的有效的基于单分子的治疗剂的强大潜力,并且作为药物发现的有价值的模型。
