Yang Ya-Chin, Wang Guan-Hsun, Chuang Ai-Yu, Hsueh Shu-Wei
Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Br J Pharmacol. 2020 Nov;177(22):5177-5194. doi: 10.1111/bph.15253. Epub 2020 Sep 28.
Perampanel is a newly approved anticonvulsant uniquely targeting AMPA receptors, which mediate the most abundant form of excitatory synaptic transmission in the brain. However, the network mechanism underlying the anti-epileptic effect of the AMPAergic inhibition remains to be explored.
The mechanism of perampanel action was studied with the basolateral amygdala network containing pyramidal-inhibitory neuronal resonators in seizure models of 4-aminopyridine (4-AP) and electrical kindling.
Application of either 4-AP or electrical kindling to the basolateral amygdala readily induces AMPAergic transmission-dependent reverberating activities between pyramidal-inhibitory neuronal resonators, which are chiefly characterized by burst discharges in inhibitory neurons and corresponding recurrent inhibitory postsynaptic potentials in pyramidal neurons. Perampanel reduces post-kindling "paroxysmal depolarizing shift" especially in pyramidal neurons and, counterintuitively, eliminates burst activities in inhibitory neurons and inhibitory synaptic inputs onto excitatory pyramidal neurons to result in prevention of epileptiform discharges and seizure behaviours. Intriguingly, similar effects can be obtained with not only the AMPA receptor antagonist CNQX but also the GABA receptor antagonist bicuculline, which is usually considered as a proconvulsant.
Ictogenesis depends on the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations tuned by dynamic glutamatergic and GABAergic transmission. The anticonvulsant effect of perampanel then stems from disruption of the coordinated network activities rather than simply decreased neuronal excitability or excitatory transmission. Positive or negative modulation of epileptic network reverberations may be pro-ictogenic or anti-ictogenic, respectively, constituting a more applicable rationale for the therapy against seizures.
吡仑帕奈是一种新获批的抗惊厥药物，它独特地作用于α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体，该受体介导大脑中最丰富形式的兴奋性突触传递。然而，AMPA能抑制的抗癫痫作用背后的网络机制仍有待探索。
在4-氨基吡啶（4-AP）诱发癫痫模型和电点燃癫痫模型中，利用包含锥体-抑制性神经元共振器的基底外侧杏仁核网络研究吡仑帕奈的作用机制。
将4-AP或电刺激施加于基底外侧杏仁核，很容易诱发锥体-抑制性神经元共振器之间依赖AMPA能传递的回响活动，其主要特征是抑制性神经元的爆发式放电以及锥体神经元相应的反复抑制性突触后电位。吡仑帕奈可减少点燃后的“阵发性去极化偏移”，尤其是在锥体神经元中，而且与直觉相反的是，它能消除抑制性神经元的爆发活动以及兴奋性锥体神经元上的抑制性突触输入，从而预防癫痫样放电和癫痫行为。有趣的是，不仅AMPA受体拮抗剂CNQX能产生类似效果，通常被认为是促惊厥剂的GABA受体拮抗剂荷包牡丹碱也能产生类似效果。
癫痫发作的产生依赖于由动态谷氨酸能和GABA能传递调节的、依赖AMPA受体的锥体-抑制性神经元网络振荡的募集。吡仑帕奈的抗惊厥作用源于对协调的网络活动的破坏，而非仅仅是神经元兴奋性或兴奋性传递的降低。癫痫网络回响的正向或负向调节可能分别是促癫痫发作或抗癫痫发作的，这为癫痫治疗提供了更适用的理论基础。
