AMPA receptors as a molecular target in epilepsy therapy.
AMPA receptors as a molecular target in epilepsy therapy.
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DOI：
10.1111/ane.12099
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Rogawski MA
中科院分区：
文献类型：
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作者：
Rogawski MA
癫痫发作是由于大脑神经元网络中间歇性异常同步放电而发生的。尽管多种非常规机制可能在癫痫同步中发挥作用，但突触连接的兴奋性谷氨酸神经元网络内的级联兴奋是一种经典机制。与整个中枢神经系统的情况一样，与癫痫相关的大脑区域内部和之间的快速突触兴奋主要由 AMPA 受体介导。通过抑制谷氨酸介导的兴奋，AMPA 受体拮抗剂可显着降低或消除体外制剂中的癫痫样活动，并在多种动物癫痫模型中提供癫痫发作保护。 NMDA 受体也可能导致癫痫样活动，但 NMDA 受体阻断不足以消除癫痫样放电。 AMPA 受体以突触可塑性、潜在学习和记忆的形式以动态方式进出突触。这些动态运动的触发因素通常是 NMDA 受体的激活。虽然 NMDA 受体拮抗剂抑制这些形式的突触可塑性，但 AMPA 受体拮抗剂不会损害突触可塑性，也不会抑制记忆形成或检索。吡仑帕奈是一种高效、口服活性非竞争性 AMPA 受体拮抗剂，其已证实的临床疗效支持了这样的观点：AMPA 受体对于人类癫痫的癫痫同步性以及癫痫放电的产生和传播至关重要。
Epileptic seizures occur as a result of episodic abnormal synchronous discharges in cerebral neuronal networks. Although a variety of nonconventional mechanisms may play a role in epileptic synchronization, cascading excitation within networks of synaptically connected excitatory glutamatergic neurons is a classical mechanism. As is the case throughout the central nervous system, fast synaptic excitation within and between brain regions relevant to epilepsy is mediated predominantly by AMPA receptors. By inhibiting glutamate-mediated excitation, AMPA receptor antagonists markedly reduce or abolish epileptiform activity in in vitro preparations and confer seizure protection in a broad range of animal seizure models. NMDA receptors may also contribute to epileptiform activity, but NMDA receptor blockade is not sufficient to eliminate epileptiform discharges. AMPA receptors move into and out of the synapse in a dynamic fashion in forms of synaptic plasticity, underlying learning and memory. Often the trigger for these dynamic movements is activation of NMDA receptors. While NMDA receptor antagonists inhibit these forms of synaptic plasticity, AMPA receptor antagonists do not impair synaptic plasticity and do not inhibit memory formation or retrieval. The demonstrated clinical efficacy of perampanel, a high-potency, orally active noncompetitive AMPA receptor antagonist, supports the concept that AMPA receptors are critical to epileptic synchronization and the generation and spread of epileptic discharges in human epilepsy.