AMPA receptors in epilepsy and as targets for antiepileptic drugs.
AMPA receptors in epilepsy and as targets for antiepileptic drugs.
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发表时间：
1999
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通讯作者：
M. Rogawski;S. Donevan
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作者：
M. Rogawski;S. Donevan
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体是神经系统中癫痫发作扩散的关键介质，也是抗癫痫药物的有希望的靶点。越来越多的证据表明 AMPA 受体可能在癫痫发生和癫痫引起的脑损伤中发挥作用。这一证据表明 AMPA 受体拮抗剂在癫痫治疗中可能具有广泛的用途。 AMPA 受体亚基的差异表达和转录后加工的变化（包括选择性剪接和前 mRNA 编辑）产生的 AMPA 受体的区域、发育和疾病相关变异，提供了多种功能不同的 AMPA 受体亚型，为选择性药物靶向提供了机会。本章讨论了四种类型的 AMPA 受体拮抗剂：(a) 竞争性 AMPA 识别位点拮抗剂，包括喹喔啉二酮类和较新的非喹喔啉二酮类拮抗剂，(b) 2,3-苯二氮卓类非竞争性（变构）拮抗剂，(c) 脱敏增强拮抗剂，例如 SCN- 拮抗剂，以及 (d) 拮抗剂 Ca(2+) 渗透性 AMPA 受体，包括聚胺酰胺节肢动物毒素及其合成类似物。竞争性和非竞争性 AMPA 受体拮抗剂是动物癫痫模型中的广谱抗惊厥药。它们对人类的有效性和安全性仍有待确定。有证据表明，这些拮抗剂可以增强 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂和常规抗癫痫药物的抗癫痫活性。这一证据表明 AMPA 受体拮抗剂的首选用途可能是联合治疗。与其他 AMPA 受体拮抗剂相比，增强脱敏作用的药物可能具有优势，因为它们优先阻断高频突触信号传导并避免抑制中间神经元上的 AMPA 受体，从而导致去抑制和兴奋性增强。越来越多的证据表明，Ca(2+) 渗透性 AMPA 受体（缺乏编辑的 GluR2 亚基）可能在癫痫发生和长期癫痫发作引起的脑损伤中发挥作用。由于 Ca(2+) 渗透性 AMPA 受体主要在 γ-氨基丁酸 (GABA) 能中间神经元中表达，因此推测某些形式的癫痫可能是由于 Ca(2+) 渗透性 AMPA 受体介导的中间神经元兴奋性毒性死亡导致 GABA 抑制减少引起的。进一步提出，选择性靶向 Ca(2+) 渗透性 AMPA 受体的药物可能具有抗癫痫和神经保护特性。某些多胺毒素及其类似物是通道阻断 AMPA 受体拮抗剂，可选择性抑制 Ca(2+) 渗透性 AMPA 受体。这些物质可能为此类拮抗剂的开发提供线索。
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are key mediators of seizure spread in the nervous system and represent promising targets for antiepileptic drugs. There is emerging evidence that AMPA receptors may play a role in epileptogenesis and in seizure-induced brain damage. This evidence suggests that AMPA receptor antagonists could have broad utility in epilepsy therapy. Regional, developmental, and disease-associated variations in AMPA receptors produced by differential expression of AMPA receptor subunits and variations in posttranscriptional processing, including alternative splicing and pre-mRNA editing, provide a diversity of functionally distinct AMPA receptor isoforms that allow opportunities for selective drug targeting. Four types of AMPA receptor antagonist are discussed in this chapter: (a) competitive AMPA recognition site antagonists, including those of the quinoxalinedione and newer nonquinoxalinedione classes, (b) 2,3-benzodiazepine noncompetitive (allosteric) antagonists, (c) desensitization enhancing antagonists, exemplified by SCN-, and (d) antagonists of Ca(2+)-permeable AMPA receptors, including polyamine amide arthropod toxins and their synthetic analogues. Competitive and noncompetitive AMPA receptor antagonists are broad-spectrum anticonvulsants in animal seizure models. Their effectiveness and safety for humans remain to be determined. There is evidence that these antagonists can potentiate the antiseizure activity of N-methyl-D-aspartate (NMDA) receptor antagonists and conventional antiepileptic drugs. This evidence suggests that the preferred use of AMPA receptor antagonists may be in combination therapies. Agents that enhance desensitization may have advantages in comparison with other AMPA receptor antagonists to the extent that they preferentially block high-frequency synaptic signaling and avoid depressing AMPA receptors on interneurons, which would lead to disinhibition and enhanced excitability. Evidence has accumulated that Ca(2+)-permeable AMPA receptors (those lacking the edited GluR2 subunit) may play a role in epileptogenesis and the brain damage occurring with prolonged seizures. Because Ca(2+)-permeable AMPA receptors are predominately expressed in gamma-aminobutyric acid (GABA)ergic interneurons, it is hypothesized that some forms of epilepsy might be caused by reduced GABA inhibition resulting from Ca(2+)-permeable AMPA receptor-mediated excitotoxic death of interneurons. It is further proposed that drugs that selectively target Ca(2+)-permeable AMPA receptors might have antiepileptogenic and neuroprotective properties. Certain polyamine toxins and their analogues are channel-blocking AMPA receptor antagonists that selectively inhibit Ca(2+)-permeable AMPA receptors. These substances might give clues to the development of such antagonists.