Department of Acute Brain Injury, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Department of Acute Brain Injury, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Neurobiol Dis. 2023 Mar;178:106027. doi: 10.1016/j.nbd.2023.106027. Epub 2023 Feb 2.
A large set of inflammatory molecules and their receptors are induced in epileptogenic foci of patients with pharmacoresistant epilepsies of structural etiologies or with refractory status epilepticus. Studies in animal models mimicking these clinical conditions have shown that the activation of specific inflammatory signallings in forebrain neurons or glial cells may modify seizure thresholds, thus contributing to both ictogenesis and epileptogenesis. The search for mechanisms underlying these effects has highlighted that inflammatory mediators have CNS-specific neuromodulatory functions, in addition to their canonical activation of immune responses for pathogen recognition and clearance. This review reports the neuromodulatory effects of inflammatory mediators and how they contribute to alter the inhibitory/excitatory balance in neural networks that underlie seizures. In particular, we describe key findings related to the ictogenic role of prototypical inflammatory cytokines (IL-1β and TNF) and danger signals (HMGB1), their modulatory effects of neuronal excitability, and the mechanisms underlying these effects. It will be discussed how harnessing these neuromodulatory properties of immune mediators may lead to novel therapies to control drug-resistant seizures.
一大组炎症分子及其受体在结构病因学药物难治性癫痫或难治性癫痫持续状态患者的致痫灶中被诱导产生。在模拟这些临床情况的动物模型中的研究表明，在前脑神经元或神经胶质细胞中特定炎症信号的激活可能改变癫痫发作阈值，从而有助于癫痫发作和癫痫发生。对这些影响背后机制的研究表明，炎症介质除了对病原体识别和清除的免疫反应的经典激活外，还具有中枢神经系统特异性的神经调节功能。本综述报告了炎症介质的神经调节作用，以及它们如何有助于改变导致癫痫发作的神经网络中的抑制/兴奋平衡。特别是，我们描述了与典型炎症细胞因子（IL-1β和 TNF）和危险信号（HMGB1）的致痫作用、它们对神经元兴奋性的调节作用以及这些作用的机制相关的关键发现。将讨论如何利用免疫介质的这些神经调节特性来开发新的治疗方法以控制耐药性癫痫发作。
