Retigabine suppresses loss of force in mouse models of hypokalaemic periodic paralysis.
Retigabine suppresses loss of force in mouse models of hypokalaemic periodic paralysis.
复制标题
DOI：
10.1093/brain/awac441
复制
发表时间：
2023-04-19
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
周期性麻痹中反复发作的无力是由肌纤维兴奋性间歇性丧失引起的，这是静息电位持续去极化的结果。通过增加纤维对钾的渗透性有利于复极化。基于这一原理，我们测试了瑞替加滨（一种钾通道开放剂）抑制低钾性周期性麻痹 (HypoPP) 低 K+ 刺激引起的力量损失的功效。瑞替加滨可以预防 HypoPP 的间歇性力量丧失。 HypoPP 的敲入突变小鼠模型（Cacna1s p.R528H 和 Scn4a p.R669H）用于确定瑞替加滨预处理是否可以防止力量损失，或者治疗后是否可以加速离体收缩测定中低 K+ 挑战的力量恢复。在我们的 HypoPP 小鼠模型中，瑞替加滨完全防止 2 mM K+ 攻击（保护）引起的力损失，NaV1.4-R669H 和 CaV1.1-R528H 的 50% 抑制浓度分别为 0.8 ± 0.13 μM 和 2.2 ± 0.42 μM。相比之下，KATP 通道开放剂吡那地尔的有效浓度高出 10 倍。应用瑞替加滨还逆转了维持在 2 mM K+ 的 HypoPP 肌肉的力量损失（救援）。我们的研究结果表明，瑞替加滨（瑞替加滨）是钾通道 KV7 家族的选择性激动剂，可有效预防低 K+ 诱导的无力发作，并促进 1 型 (Cacna1s) 和 2 型 (Scn4a) HypoPP 小鼠模型持续力量丧失的恢复。低微摩尔范围内发生了对力损失的实质性保护，完全在瑞替加滨的治疗窗内。奎尼奥内斯等人。研究表明，在低钾性周期性麻痹小鼠模型中，钾通道开放剂瑞替加滨既可以保护肌肉免受力量损失，又可以加速从持续力量损失中恢复。
Recurrent episodes of weakness in periodic paralysis are caused by intermittent loss of muscle fibre excitability, as a consequence of sustained depolarization of the resting potential. Repolarization is favoured by increasing the fibre permeability to potassium. Based on this principle, we tested the efficacy of retigabine, a potassium channel opener, to suppress the loss of force induced by a low-K+ challenge in hypokalaemic periodic paralysis (HypoPP). Retigabine can prevent the episodic loss of force in HypoPP. Knock-in mutant mouse models of HypoPP (Cacna1s p.R528H and Scn4a p.R669H) were used to determine whether pre-treatment with retigabine prevented the loss of force, or post-treatment hastened recovery of force for a low-K+ challenge in an ex vivo contraction assay. Retigabine completely prevents the loss of force induced by a 2 mM K+ challenge (protection) in our mouse models of HypoPP, with 50% inhibitory concentrations of 0.8 ± 0.13 μM and 2.2 ± 0.42 μM for NaV1.4-R669H and CaV1.1-R528H, respectively. In comparison, the effective concentration for the KATP channel opener pinacidil was 10-fold higher. Application of retigabine also reversed the loss of force (rescue) for HypoPP muscle maintained in 2 mM K+. Our findings show that retigabine, a selective agonist of the KV7 family of potassium channels, is effective for the prevention of low-K+ induced attacks of weakness and to enhance recovery from an ongoing loss of force in mouse models of type 1 (Cacna1s) and type 2 (Scn4a) HypoPP. Substantial protection from the loss of force occurred in the low micromolar range, well within the therapeutic window for retigabine. Quiñonez et al. show that the potassium channel opener retigabine can both protect muscle from a loss of force and hasten recovery from an ongoing loss of force in a mouse model of hypokalaemic periodic paralysis.
登录
查看更多内容
影响因子：
--
作者：
Su, Tzu-Rong;Zei, Wen-Shan;Lin, Min-Jon
通讯作者：
Lin, Min-Jon
影响因子：
10.9
作者：
Shkolnik, Tali Garin;Feuerman, Hana;Hodak, Emmilia
通讯作者：
Hodak, Emmilia
影响因子：
15.9
作者：
Wu, Fenfen;Mi, Wentao;Cannon, Stephen C.
通讯作者：
Cannon, Stephen C.
影响因子：
9.9
作者：
Bulman, DE;Scoggan, KA;Ebers, GC
通讯作者：
Ebers, GC
影响因子：
9.9
作者：
Matthews, E.;Portaro, S.;Hanna, M. G.
通讯作者：
Hanna, M. G.