Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA; Department of Psychiatry, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Neurobiol Dis. 2024 Oct 1;200:106633. doi: 10.1016/j.nbd.2024.106633. Epub 2024 Aug 6.
The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABA receptor (GABAR)-mediated inhibition has a central role among the mechanisms underlying brain damage and the ensuing epilepsy and anxiety. During SE, calcium influx primarily via ionotropic glutamate receptors activates signaling cascades which trigger a rapid internalization of synaptic GABARs; this weakens inhibition, exacerbating seizures and excitotoxicity. GABAergic interneurons are more susceptible to excitotoxic death than principal neurons. During the latent period of epileptogenesis, the aberrant reorganization in synaptic interactions that follow interneuronal loss in injured brain regions, leads to the formation of hyperexcitable, seizurogenic neuronal circuits, along with disturbances in brain oscillatory rhythms. Reduction in the spontaneous, rhythmic "bursts" of IPSCs in basolateral amygdala neurons is likely to play a central role in anxiogenesis. Protecting interneurons during SE is key to preventing both epilepsy and anxiety. Antiglutamatergic treatments, including antagonism of calcium-permeable AMPA receptors, can be expected to control seizures and reduce excitotoxicity not only by directly suppressing hyperexcitation, but also by counteracting the internalization of synaptic GABARs. Benzodiazepines, as delayed treatment of SE, have low efficacy due to the reduction and dispersion of their targets (the synaptic GABARs), but also because themselves contribute to further reduction of available GABARs at the synapse; furthermore, benzodiazepines may be completely ineffective in the immature brain.
癫痫持续状态（SE）在非癫痫患者中的触发因素多种多样，从特发性原因到接触化学惊厥剂。无论其病因如何，长时间的 SE 都会导致严重的脑损伤，通常会导致癫痫的发展，而癫痫常常伴随着焦虑增加。GABA 受体（GABAR）介导的抑制在脑损伤和随之而来的癫痫和焦虑的机制中起着核心作用。在 SE 期间，通过离子型谷氨酸受体的钙内流主要激活信号级联反应，从而触发突触 GABAR 的快速内化；这削弱了抑制作用，加剧了发作和兴奋性毒性。GABA 能中间神经元比主神经元更容易受到兴奋性毒性死亡的影响。在癫痫发生的潜伏期期间，损伤脑区中 GABA 能中间神经元丧失后突触相互作用的异常重组导致兴奋性过高、致痫性神经元回路的形成，以及脑振荡节律的紊乱。基底外侧杏仁核神经元中 IPSC 的自发性、节律性“爆发”减少，可能在焦虑发生中起核心作用。在 SE 期间保护中间神经元是预防癫痫和焦虑的关键。抗谷氨酸能治疗，包括钙通透性 AMPA 受体拮抗剂，不仅可以通过直接抑制过度兴奋，还可以通过对抗突触 GABAR 的内化来控制癫痫发作和减少兴奋性毒性。苯二氮䓬类药物作为 SE 的延迟治疗，由于其靶标（突触 GABAR）的减少和分散，以及由于它们本身导致突触处可用 GABAR 的进一步减少，因此疗效较低；此外，苯二氮䓬类药物在不成熟的大脑中可能完全无效。
