State University of New York at Buffalo, Center for Hearing and Deafness, Buffalo, NY 14214, United States.
Physiol Behav. 2011 Oct 24;104(5):873-9. doi: 10.1016/j.physbeh.2011.05.022. Epub 2011 May 27.
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 10 mg/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.
目前，尽管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过度兴奋，已经做出了许多努力，但仍没有有效的治疗慢性耳鸣的药理学疗法。本研究的目的是评估一种新型具有钾通道活性的抗焦虑药在抑制动物水杨酸盐诱导的耳鸣中的治疗效果。Kv7 钾通道存在于外周和中枢听觉系统中，据信它们可以调节神经活动。Maxipost 是一种通过正调控 Kv7.2-Kv7.5 通道来减轻过度兴奋的化合物，它被用于有水杨酸盐诱导的耳鸣行为证据的大鼠中。耳鸣通过我们之前建立的动物模型——条件性回避饮水来测量，这是一种范式，其中大鼠被训练只在安静时饮水，并在有声音时抑制饮水。单独的水杨酸盐显著抑制了安静时的舔舐，但对声音时的舔舐没有影响；这与耳鸣的存在一致。10mg/kg 的 Maxipost 抑制了耳鸣的行为证据，因为它完全逆转了水杨酸盐对安静时舔舐的抑制。出乎意料的是，Maxipost 的 R-对映体 R-Maxipost 没有抗焦虑作用，并且负调控 Kv7.2-Kv7.5，也抑制了耳鸣的行为证据。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，似乎 Maxipost 和 R-xMaxipost 之间存在共同的机制，例如抑制 Kv7.1 通道或激活 BK 通道，或者两种化合物都具有的一些新的共同机制，这两种化合物都以剂量依赖的方式完全消除了耳鸣的行为证据。进一步的研究需要使用特定的 BK 通道激动剂/拮抗剂来确定这些通道对其他形式的耳鸣的贡献或确定可能与耳鸣有关的新靶点。
