Pharmacodynamics of potassium channel openers in cultured neuronal networks

Abstract

a b s t r a c tA novel class of drugs -potassium (K þ ) channel openers or activators -has recently been shown to cause anticonvulsive and neuroprotective effects by activating hyperpolarizing K þ currents, and therefore, mayshow efficacy for treating tinnitus. This study presents measurements of the modulatory effects of four K þ channel openers on the spontaneous activity and action potential waveforms of neuronal networks. The networks were derived from mouse embryonic auditory cortices and grown on microelectrode arrays. Pentylenetetrazol was used to create hyperactivity states in the neuronal networks as a first approximation for mimicking tinnitus or tinnitus-like activity. We then compared the pharmacodynamics of the four channel activators, retigabine and flupirtine (voltage-gated K þ channel K V 7 activators), NS1619 and isopimaric acid ("big potassium" BK channel activators). The EC 50 of retigabine, flupirtine, NS1619, and isopimaric acid were 8.0, 4.0, 5.8, and 7.8 mM, respectively. The reduction of hyperactivity compared to the reference activity was significant. The present results highlight the notion of re-purposing the K þ channel activators for reducing hyperactivity of spontaneously active auditory networks, serving as a platform for these drugs to show efficacy toward target identification, prevention, as well as treatment of tinnitus.

Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels

“…A variety of resin acids, and derivatives of resin acids, reduce cellular excitability in sensory neurons (Ottosson et al, 2015), prevent hyper-excitability in auditory cortical networks (Wu et al, 2014) and moderately inhibit epileptic activity in hippocampal neurons (Kobayashi et al, 2008). In my thesis work, we show that IPA also reduces the action-potential frequency of cardiomyocytes by acting on several voltage-gated ion channels.…”

“…The naturally occurring resin acid, isopimaric acid (IPA), that opens the Shaker KV channel (Ottosson et al, 2015), the BK channel (Imaizumi et al, 2002), and reduces the action potential frequency in neurons (Kobayashi et al, 2008;Wu et al, 2014), was used to explore the effect of a resin acid on cardiac excitability, and several cardiac ion currents.…”

Synthesis and Bioactivity Evaluation of Acylthiourea Derivatives Based on Isopimaric Acid

“…关于异海松酸的生物活性研究 报道较多的是其活化大型钙离子激活的钾离子(BK)通 道的活性 [1,2] . 进一步研究表明, 异海松酸作为 BK 通道 的活化剂可以调控初级成骨细胞的生长和矿化 [3] , 并降 低小鼠听觉神经网络自发活动的多动症和改善患阿尔 茨海默病小鼠的认知功能, 从而对神经活性多动症和阿 尔茨海默病具有潜在的治疗效果 [4,5] . 其次, 异海松酸对 结核病毒具有显著的疗效 [6] , 并对爱博斯坦巴尔病毒 也显示出抑制效果 [7] .…”

Potassium channels as promising new targets for pharmacologic treatment of tinnitus: Can Internet-based ‘crowd sensing’ initiated by patients speed up the transition from bench to bedside?

“…By shifting the voltage-dependent opening of Kv7 channels to more negative voltages [7] retigabine increases channel activity, which leads to reduced excitability and seizure activity. [8] As the clinical use of retigabine is limited by its side effects, efforts have been made to develop improved Kv7.2/3 activators. By incorporating a fluorine substituent the compound SF0034 has been synthesized, which acts more specifically and more potently on Kv7.2/3 channels.…”

“…The analgesic flupirtine exerts an effect on neuronal Kv7 channels which is similar to that of retigabine. [8] In one open trial, in which the effect of flupirtine was investigated on tinnitus severity and loudness, only one out of 24 investigated patients reported a positive effect after 3 weeks of flupirtine intake at a dosage of 200 mg/day. [15] No results from retigabine treatment in tinnitus have been published in the scientific literature and no ongoing trial with retigabine is registered for this application at ClinicalTrials.…”