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首页> 外文期刊>The European Journal of Neuroscience >AMPA receptors as drug targets in neurological disease - advantages, caveats, and future outlook
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AMPA receptors as drug targets in neurological disease - advantages, caveats, and future outlook

机译：AMPA受体作为神经系统疾病的药物靶标-优势，警告和未来展望

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Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor function are altered, thus making AMPA receptors potential therapeutic targets for clinical intervention. The work summarized in this review suggests a link between AMPA receptor function and debilitating neuropathologies, and discusses the current state of therapies targeting AMPA receptors in four diseases. In amyotrophic lateral sclerosis, AMPA receptors allow cytotoxic levels of calcium into neurons, leading to motor neuron death. Likewise, in some epilepsies, overactivation of AMPA receptors leads to neuron damage. The same is true for ischemia, where oxygen deprivation leads to excitotoxicity. Conversely, Alzheimer's disease is characterized by decreased AMPA activation and synapse loss. Unfortunately, many clinical studies have had limited success by directly targeting AMPA receptors in these diseases. We also discuss how the use of AMPA receptor modulators, commonly known as ampakines, in neurological diseases initially seemed promising in animal studies, but mostly ineffective in clinical trials. We propose that indirectly affecting AMPA receptors, such as by modulating transmembrane AMPA receptor regulatory proteins or, more generally, by regulating glutamatergic transmission, may provide new therapeutic potential for neurological disorders.
机译：脑中大多数兴奋性传递是由离子型谷氨酸受体的AMPA受体亚型介导的。在许多神经系统疾病中，突触结构和AMPA受体功能发生改变，因此使AMPA受体成为临床干预的潜在治疗靶标。这篇综述中的工作提出了AMPA受体功能与衰弱性神经病理学之间的联系，并讨论了针对四种疾病中针对AMPA受体的疗法的当前状态。在肌萎缩性侧索硬化症中，AMPA受体可使钙进入神经元的细胞毒性水平升高，导致运动神经元死亡。同样，在某些癫痫病中，AMPA受体的过度激活会导致神经元损伤。对于缺氧导致兴奋性毒性的局部缺血也是如此。相反，阿尔茨海默氏病的特征是AMPA激活和突触损失减少。不幸的是，许多临床研究通过直接针对这些疾病中的AMPA受体取得了有限的成功。我们还讨论了在动物疾病中最初在神经系统疾病中使用AMPA受体调节剂（通常称为ampakines）如何在动物研究中看起来很有希望，但在临床试验中大多无效。我们提出间接影响AMPA受体，例如通过调节跨膜AMPA受体调节蛋白，或更普遍地，通过调节谷氨酸能传递，可能为神经系统疾病提供新的治疗潜力。

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