Inhibition of seizures and neuron excitability by acid-sensing ion channels

通过酸敏感离子通道抑制癫痫发作和神经元兴奋性

基本信息

批准号：
7384338
负责人：
John A Wemmie
金额：
$ 19.69万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-14 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7384338
关键词：
ASIC channel Acidosis Acids Action Potentials Affect Air Antiepileptic Agents Attenuated Biological Models Blood - brain barrier anatomy Brain Breathing Carbon Dioxide Carbonic Anhydrase Inhibitors Cells Data Depth Development Disease Electroencephalography Epilepsy Fostering Gene Mutation Generations Genes Genotype Goals Hippocampus (Brain)Human Ion Channel Kinetics Knock-out Knockout Mice Knowledge Laboratories Lead Link Measures Mediating Medical Membrane Potentials Molecular Morbidity - disease rate Mus Neurons Numbers Patients Play Positioning Attribute Potassium Channel Property Protein Overexpression Protons Range Refractory Refractory Disease Relative (related person)Research Research Personnel Role Seizures Severities Slice Source Testing Therapeutic Transgenic Mice Wild Type Mouse Work extracellular improved in vivo insight interest mortality novel novel therapeutics prevent programs receptor research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Seizure disorders cause significant morbidity and mortality, and many cases are refractory to current medical management. Thus, improved treatments are needed. Therapeutic advances might be developed from a better understanding of the antiepileptic mechanisms of brain acidosis. It has long been known that low pH effectively inhibits seizures and reduces neuron excitability, but the molecular mechanisms underlying these effects are poorly understood. The recent identification of proton receptors in the brain may provide a molecular link between brain pH and seizures. It was recently found that one of these receptors, the acid sensing ion channel ASIC1a is required for acid-evoked currents in central neurons. And consistent with an inhibitory effect on seizures, preliminary data indicate overexpressing ASIC1a in mice attenuates seizures. In contrast, disrupting ASIC1a makes seizures worse. Together, these observations suggest the hypothesis that ASIC1a mediates the antiepileptic effects of central acidosis and reduces neuron excitability. To test this hypothesis three aims are planned. The first aim will test whether ASIC1a mediates antiepileptic effects of CO2, which rapidly crosses the blood-brain barrier and lowers central pH. Wild-type mice, ASIC1a null mice, and ASIC1a overexpressing transgenic mice will be injected with a chemoconvulsant and the anti-epileptic effects of CO2 relative to air will be compared between genotypes. The results will provide an indication of whether the anti-epileptic properties of ASIC1a and CO2 are related. The second aim will test whether ASIC1a mediates the antiepileptic effects of acid in brain slices where pH can be better controlled. The third aim will test the effects of ASIC1a on acid inhibition of action potentials in cultured hippocampal neurons. Preliminary data suggest ASIC1a may inhibit action potentials, which may help explain how ASIC1a inhibits seizures in vivo. Together these experiments will provide important insight into the historically well established but poorly understood antiepileptic effects of acid. They will also lead to additional mechanistic studies to clarify in more depth how ASIC1a exerts its antiepileptic effects. Importantly, these studies may also suggest ASIC1a as a novel therapeutic target for inhibiting seizures in patients. Identifying novel and broad antiepileptic mechanisms may be especially beneficial to patients with refractory disease. Seizures disorders cause significant morbidity and mortality and are often refractory to medical management. Studying novel features of seizure inhibition may lead to treatments with alternative mechanisms of action. In this application we explore the seizure inhibiting effects of a poorly understood gene, acid-sensing ion channel 1a, and we test whether ASIC1a contributes to the well-established but poorly understood antiepileptic effects of brain acidosis. These studies have the potential to foster the development of Asic1a antagonists as a novel therapeutic approach to seizures.

描述（由申请人提供）：癫痫发作疾病会引起明显的发病率和死亡率，许多病例对当前的医疗管理是难治性的。因此，需要改进的治疗方法。可以从更好地理解脑酸中毒的抗癫痫性机制来发展治疗性进步。早就知道，低pH值有效抑制癫痫发作并降低神经元兴奋性，但是这些作用的分子机制知之甚少。脑中质子受体的最新鉴定可能会在脑pH和癫痫发作之间提供分子联系。最近发现，其中一种受体是中央神经元中酸诱发的电流所需的酸离子通道ASIC1A。并且与对癫痫发作的抑制作用一致，初步数据表明小鼠中的ASIC1A过表达会减弱癫痫发作。相反，破坏ASIC1A会使癫痫发作更糟。总之，这些观察结果表明ASIC1A介导了中心酸中心的抗癫痫作用并降低了神经元的兴奋性。为了检验该假设，计划了三个目标。第一个目标将测试ASIC1A是否介导CO2的抗癫痫作用，该二氧化碳迅速越过血脑屏障并降低了中央pH值。野生型小鼠，ASIC1A无效小鼠和ASIC1A过表达的转基因小鼠将与化学弹药抗体一起注射，并且在基因型之间将比较二氧化碳相对于空气的抗癫痫作用。结果将表明ASIC1A和CO2的抗癫痫特性是否相关。第二个目标将测试ASIC1A是否介导了可以更好地控制pH的脑切片中酸的抗癫痫作用。第三个目标将测试ASIC1A对培养的海马神经元酸抑制作用电位的影响。初步数据表明ASIC1A可能会抑制作用电位，这可能有助于解释ASIC1A如何抑制体内癫痫发作。这些实验将共同提供对酸的历史悠久但知识熟悉的抗癫痫作用的重要见解。它们还将导致更多的机械研究，以更深入地阐明ASIC1A如何发挥其抗癫痫作用。重要的是，这些研究还可能表明ASIC1A是抑制患者癫痫发作的新型治疗靶标。识别新颖和广泛的抗癫痫性机制可能对难治性疾病患者特别有益。癫痫发作疾病会引起严重的发病率和死亡率，并且通常对医疗管理难治性。研究癫痫发作抑制的新特征可能会导致具有替代作用机理的治疗方法。在此应用中，我们探讨了癫痫发作的癫痫发作，对酸敏离子通道1a的抑制作用，并测试ASIC1A是否有助于脑酸中毒的抗癫痫效应，但促成了良好的抗癫痫效应。这些研究有可能促进ASIC1A拮抗剂的发展，作为一种新型的癫痫治疗方法。