Effects of the potassium ion channel modulators BMS-204352 Maxipost and its R-enantiomer on salicylate-induced tinnitus in rats.
Effects of the potassium ion channel modulators BMS-204352 Maxipost and its R-enantiomer on salicylate-induced tinnitus in rats.
复制标题
钾离子通道调节剂 BMS-204352 Maxipost 及其 R-对映体对水杨酸盐诱导的大鼠耳鸣的影响。
DOI：
10.1016/j.physbeh.2011.05.022
复制
发表时间：
2011
影响因子：
2.9
通讯作者：
Salvi,Richard
中科院分区：
文献类型：
--
作者：
Lobarinas,Edward;Dalby-Brown,William;Stolzberg,Daniel;Mirza,NaheedR;Allman,BrianL;Salvi,Richard
目前，尽管许多临床研究和最近的动物研究使用化合物来增强内源性抑制或减少中枢多动性，但还没有有效的药物治疗慢性耳鸣。本研究的目的是评价一种具有钾通道活性的新型抗焦虑药对水杨酸诱导的动物耳鸣的治疗效果。Kv7钾通道存在于外周和中枢听觉系统中，它们被认为可以调节神经活动。maximpost是一种通过正向调节Kv7.2-Kv7.5通道来减弱高兴奋性的化合物，用水杨酸盐诱导耳鸣的行为证据给药。耳鸣是用我们之前建立的动物模型来测量的，时间表诱导的烦渴回避条件反射，这是一个范式，大鼠只在安静的时候喝水，在有声音的情况下抑制喝水。单独使用水杨酸盐显著抑制安静状态下的舔舐，但对声音状态下的舔舐没有影响；结果与耳鸣的存在一致。10mg/kg的最大剂量抑制了耳鸣的行为证据，因为它完全逆转了水杨酸盐在安静时对舔舐的抑制。出乎意料的是，Maxipost的r -对映体，R-Maxipost，没有抗焦虑作用，负调节Kv7.2-Kv7.5，也抑制耳鸣的行为证据。我们最初的假设是Kv7.2-Kv7.5通道可能在耳鸣产生中起关键作用，而Maxipost而不是R-Maxipost会抑制耳鸣；然而，Maxipost和R-xMaxipost之间似乎有一种共同的机制，如抑制Kv7.1通道或激活BK通道或两种化合物共同的一些新机制，是水杨酸诱导耳鸣的基础，因为两种化合物都以剂量依赖的方式完全消除耳鸣的行为证据。有必要进一步研究特异性BK通道激动剂/拮抗剂，以确定这些通道对其他形式耳鸣的贡献，或确定可能与耳鸣相关的新靶点。
Currently, there are no effective pharmacological therapies for chronic tinnitus despite a number of efforts from clinical studies and more recently, studies in animals using compounds to enhance endogenous inhibition or reduce central hyperactivity. The purpose of the current study was to evaluate the therapeutic efficacy of a novel anxiolytic with potassium channel activity in suppressing salicylate induced tinnitus in animals. Kv7 potassium channels are present in the peripheral and central auditory system where they are believed to modulate neural activity. Maxipost, a compound which attenuates hyperexcitability via positive modulation of Kv7.2–Kv7.5 channels, was administered to rats with behavioral evidence of salicylate induced tinnitus. Tinnitus was measured using our previously established animal model, Schedule Induced Polydipsia Avoidance Conditioning, a paradigm where rats were conditioned to drink only during quiet and suppress drinking in the presence of sound. Salicylate alone significantly suppressed licks in quiet but had no effect on licks in sound; results consistent with the presence of tinnitus. Maxipost at 10mg/kg suppressed behavioral evidence of tinnitus as it completely reversed salicylate's suppression of licks in quiet. Unexpectedly, the R-enantiomer of Maxipost, R-Maxipost, which has no anxiolytic effects and negatively modulates Kv7.2–Kv7.5, also suppressed behavioral evidence of tinnitus. Our original hypothesis was that Kv7.2–Kv7.5 channels might play a key role in tinnitus generation and that Maxipost but not R-Maxipost would suppress tinnitus; however, it appears that a shared mechanism between Maxipost and R-xMaxipost, such as inhibition of Kv7.1 channels or activation of BK channels or some novel mechanism common to both compounds, underlies salicylate induced tinnitus as both compounds completely abolished behavioral evidence of tinnitus in a dose-dependent manner. Further studies with specific BK channel agonists/antagonists are necessary to determine the contribution of these channels to other forms of tinnitus or determine novel targets that could be related to tinnitus.